U.S. patent number 7,423,035 [Application Number 11/125,757] was granted by the patent office on 2008-09-09 for substituted cycloalkyl derivatives, process for the manufacture thereof and use thereof as medicament.
This patent grant is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Thierry Bouyssou, Christoph Hoenke, Ingo Konetzki, Philipp Lustenberger, Klaus Rudolf, Marco Santagostino, Andreas Schnapp.
United States Patent |
7,423,035 |
Konetzki , et al. |
September 9, 2008 |
Substituted cycloalkyl derivatives, process for the manufacture
thereof and use thereof as medicament
Abstract
The present invention relates to compounds of formula 1
##STR00001## wherein the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, n, m and X may have the
meanings given in the claims and in the specification, and the use
thereof as pharmaceutical compositions, particularly for the
treatment of inflammatory and obstructive respiratory
complaints.
Inventors: |
Konetzki; Ingo (Warthausen,
DE), Bouyssou; Thierry (Mietingen, DE),
Lustenberger; Philipp (Warthausen, DE), Schnapp;
Andreas (Biberach, DE), Hoenke; Christoph
(Ingelheim, DE), Rudolf; Klaus (Warthausen,
DE), Santagostino; Marco (Magenta, IT) |
Assignee: |
Boehringer Ingelheim International
GmbH (Ingelheim, DE)
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Family
ID: |
35456777 |
Appl.
No.: |
11/125,757 |
Filed: |
May 10, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20050261286 A1 |
Nov 24, 2005 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60578568 |
Jun 10, 2004 |
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Foreign Application Priority Data
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May 13, 2004 [EP] |
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04425343 |
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Current U.S.
Class: |
514/230.5;
544/105 |
Current CPC
Class: |
C07C
215/60 (20130101); C07D 215/227 (20130101); C07C
311/08 (20130101); C07D 265/36 (20130101); A61P
11/06 (20180101); C07C 215/68 (20130101); C07C
217/74 (20130101); C07C 2601/14 (20170501); C07C
2601/02 (20170501); C07C 2601/08 (20170501) |
Current International
Class: |
C07D
265/36 (20060101); A61K 31/138 (20060101); A61K
31/538 (20060101) |
Field of
Search: |
;544/105 ;514/230.5 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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973887 |
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Oct 1964 |
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GB |
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9533724 |
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Dec 1995 |
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WO |
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Other References
Vippagunta et al, "Crystalline Solids" Advanced Drug Delivery
Reviews, vol. 48, pp. 3-26 (2001). cited by examiner .
GavezzotU, "Are Crystal Structures Predictable?" Accounts of
Chemical Research, vol. 27, pp. 309-314 (1994). cited by examiner
.
Temple et al.; Adrenergic Sulfonanilides. 4. Centrally Active
beta-adrenergic agonists; Journal of Medicinal Chemistry; 1976;
vol. 19; No. 5; pp. 626-633. cited by other .
International Search Report, Form PCT/ISA/210, for corresponding
PCT/EP2005/005025 (2005). cited by other .
Airapetyan et al.; Isoquinoline derivatives. XXVI. Synthesis of
N-arylalkanol derivatives of 4-spiro-substituted
1,2,3,4-tethydroisoquinolines and
1-(3,4-dimethoxyphenyl)-1-cycloalkylmethylamines with
beta-adrenoblocking properties; Database Chemabs; Chemical
Abstracts Service; Columbus, OH; 1988; Database accession No.
1988:37609; abstract only. cited by other .
Bertus et al.; Ti(II)-Mediated Conversion of a-Heterosubstituted
(O, N, S) Nitriles to Functionalized Cyclopropylamines. Effect of
Chelation on the Cyclopropanation Step; Journal of Organic
Chemistry; 2002; vol. 67; pp. 3965-3968. cited by other .
Hass et al.; Carbon Aralkylations of Nitro Paraffins: Journal of
Organic Chemistry; 1949; vol. 71; pp. 2290-2291. cited by
other.
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Primary Examiner: Habte; Kahsay T
Attorney, Agent or Firm: Morris; Michael P. Devlin;
Mary-Ellen M.
Parent Case Text
This application claims priority under 35 USC 119(e) to U.S.
Provisional Application 60/578,568, filed Jun. 10, 2004.
Claims
The invention claim is:
1. A compound of formula 1a ##STR00077## wherein n denotes 0 or 1;
m denotes 1, 2, 3 or 4; X denotes a single bond or one of the
double-bonded groups C.sub.2-C.sub.6-alkenylene,
--O--C.sub.1-C.sub.6-alkylene, --NH--C.sub.1-C.sub.6-alkylene,
--S--C.sub.1-C.sub.6-alkylene or C.sub.1-C.sub.6-alkylene; R.sup.3
and R.sup.4 which may be identical or different denote a group
selected from hydrogen, OH, halogen, --C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-hydroxyalkyl,
NH.sub.2, NH(--C.sub.1-C.sub.4-alkyl) and
N(--C.sub.1-C.sub.4-alkyl).sub.2; R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, which may be identical or different, denote hydrogen,
OR.sup.9, --C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-haloalkyl,
--C.sub.1-C.sub.6-hydroxyalkyl, --C.sub.3-C.sub.6-cycloalkyl,
--C.sub.3-C.sub.6-hydroxycycloalkyl, --CN, NO.sub.2, --COR.sup.9,
--COOR.sup.9, --CONR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10COR.sup.9, --NR.sup.10SO.sub.2R.sup.12, --SR.sup.12,
--SOR.sup.12, --SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11 or
halogen, or two of the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, if they are located vicinally to the substituting phenyl
ring, together form a double-bonded group selected from
C.sub.2-C.sub.6-alkylene, C.sub.2-C.sub.6-alkenylene and
--O--C.sub.1-C.sub.6-alkylene-O-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
--C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkoxy, OH, or halogen;
R.sup.9 denotes hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene; R.sup.10 and
R.sup.11 which may be identical or different, denote hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene; R.sup.12 denotes
C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene, optionally in the
form of the individual optical isomers, mixtures of the individual
enantiomers or racemates, in the form of the free bases or the
corresponding acid addition salts thereof with pharmacologically
acceptable acids.
2. The compound of formula 1a according to claim 1, wherein n
denotes 0 or 1; m denotes 1, 2, 3 or 4; X denotes a single bond or
one of the double-bonded groups C.sub.2-C.sub.4-alkenylene,
--O--C.sub.1-C.sub.4-alkylene, --NH--C.sub.1-C.sub.4-alkylene,
--S--C.sub.1-C.sub.4-alkylene or C.sub.1-C.sub.4-alkylene; R.sup.3
and R.sup.4 which may be identical or different denote a group
selected from hydrogen, OH, halogen, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-haloalkyl, --C.sub.1-C.sub.4-hydroxyalkyl,
NH.sub.2, NH(--C.sub.1-C.sub.4-alkyl) and
N(--C.sub.1-C.sub.4-alkyl).sub.2; R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, which may be identical or different, denote hydrogen,
OR.sup.9, --C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-haloalkyl,
--C.sub.1-C.sub.4-hydroxyalkyl, --C.sub.3-C.sub.6-cycloalkyl,
--C.sub.3-C.sub.6-hydroxycycloalkyl, --CN, NO.sub.2, --COR.sup.9,
--COOR.sup.9, --CONR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10COR.sup.9, --NR.sup.10SO.sub.2R.sup.12, --SR.sup.12,
--SOR.sup.12, --SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11,
fluorine, chlorine or bromine, or two of the groups R.sup.5,
R.sup.6, R.sup.7 and R.sup.8, if they are located vicinally to the
substituting phenyl ring, together form a double-bonded group
selected from C.sub.2-C.sub.4-alkylene, C.sub.2-C.sub.4-alkenylene
and --O--C.sub.1-C.sub.4-alkylene-O-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
methyl, methoxy, OH, fluorine, chlorine or bromine; R.sup.9 denotes
hydrogen, methyl, ethyl, phenyl, naphthyl, benzyl, naphthylmethyl
or 2-phenylethyl; R.sup.10 and R.sup.11 which may be identical or
different, denote hydrogen, methyl, ethyl, phenyl, naphthyl,
naphthylmethyl, benzyl or 2-phenylethyl; R.sup.12 denotes methyl,
ethyl, phenyl, naphthyl, naphthylmethyl, benzyl or 2-phenylethyl,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the free
bases or the corresponding acid addition salts thereof with
pharmacologically acceptable acids.
3. The compound of formula 1a according to claim 1, wherein n
denotes 0 or 1; m denotes 1, 2, 3 or 4; X denotes a single bond or
one of the double-bonded groups --CH.sub.2, --CH.sub.2--CH.sub.2,
--CH.sub.2--CH.sub.2-CH.sub.2, --CH.dbd.CH, --CH.sub.2--CH.dbd.CH,
--CH.sub.2--O, --CH.sub.2--CH.sub.2--O, --CH.sub.2--NH.sub.2,
--CH.sub.2--CH.sub.2--NH.sub.2--; R.sup.3 and R.sup.4 which may be
identical or different denote a group selected from hydrogen, OH,
fluorine, chlorine, bromine, methyl, ethyl, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2--CH.sub.2--OH, --CH.sub.2--OH,
NH.sub.2, NH(methyl) and N(methyl).sub.2; R.sup.5, R.sup.6, R.sup.7
and R.sup.8, which may be identical or different, denote hydrogen,
OH, methyl, ethyl, propyl, butyl, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2--CH.sub.2F, --CH.sub.2--CHF.sub.2,
--CH.sub.2--CF.sub.3, --CH.sub.2--CH.sub.2--OH, --CH.sub.2--OH,
cyclpropyl, cyclobutyl, cyclopentyl, HO-cyclpropyl, HO-cyclobutyl,
HO-cyclopentyl, --CN, NO.sub.2, --COphenyl, --COOmethyl,
--COOethyl, --CONH.sub.2, --CONHmethyl, --CONHphenyl, --CONHbenzyl,
--CON(methyl).sub.2, NH.sub.2, NH(methyl), N(methyl).sub.2,
--NHCOmethyl, --NHCOphenyl, --NHSO.sub.2methyl, --NHSO.sub.2phenyl,
--NHSO.sub.2-phenyl-CH.sub.3, --SO.sub.2methyl, --SO.sub.2-phenyl,
--SO.sub.2-phenyl-CH.sub.3, --SO.sub.2NH.sub.2, fluorine, chlorine
or bromine, or two of the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, if they are located vicinally to the substituting phenyl
ring, together form a double-bonded group selected from
--CH.sub.2--CH.sub.2--CH.sub.2,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2, --CH.sub.2--CH.dbd.CH,
--CH.dbd.CH--CH.dbd.CH, --O--CH.sub.2--O-- and
--O--CH.sub.2--CH.sub.2--O-- wherein in each case one or 2 hydrogen
atoms may be replaced by one or two groups selected from among
methyl, methoxy, OH or fluorine, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids.
4. The compound of formula 1a according to claim 1, wherein X
denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2CH.sub.2, --CH.sub.2--O, --O--CH.sub.2-- and
--CH.sub.2; and wherein the groups R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, n and m may have the meanings given in
claims 1 to 3, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids.
5. The compound of formula 1a according claim 1, wherein the groups
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, n, m and X
may have the meanings given in claims 1 to 3, optionally in the
form of the individual optical isomers, mixtures of the individual
enantiomers or racemates, in the form of the free bases or the
corresponding acid addition salts thereof with pharmacologically
acceptable acids.
6. The compound of formula 1a according to claim 1, wherein R.sup.3
and R.sup.4 which may be identical or different denote a group
selected from hydrogen, OH, fluorine, chlorine, bromine, methyl,
ethyl, CHF.sub.2, CH.sub.2F, CF.sub.3, --CH.sub.2--CH.sub.2--OH,
--CH.sub.2--OH, NH.sub.2, NHmethyl, NHethyl, N(methyl).sub.2 and
N(ethyl).sub.2, and wherein the groups R.sup.1, R.sup.2, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, n, m and X may have the meanings given
in claims 1 to 3, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids.
7. The compound of formula 1a according to claim 1, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, ethyl, propyl, butyl,
CHF.sub.2, CH.sub.2F, CF.sub.3, --CH.sub.2--CH.sub.2--OH,
--CH.sub.2--OH, methyloxy, ethyloxy, propyloxy, butyloxy,
cyclopropyl, hydroxycyclopropyl, NH.sub.2, NHmethyl,
N(methyl).sub.2, fluorine, chlorine or bromine, or two of the
groups R.sup.5, R.sup.6, R.sup.7 and R.sup.8, if they are located
vicinally to the substituting phenyl ring, denote the double-bonded
group --CH.dbd.CH--CH.dbd.CH-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
methyl, methoxy, OH, fluorine, chlorine or bromine, and wherein the
groups R.sup.3, R.sup.4 n, m and X may have the meanings given in
claim 1, optionally in the form of the individual optical isomers,
mixtures of the individual enantiomers or racemates, in the form of
the free bases or the corresponding acid addition salts thereof
with pharmacologically acceptable acids.
8. The compound of formula 1a according to claim 1, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, ethyl, propyl, butyl,
CHF.sub.2, CH.sub.2F, CF.sub.3, methyloxy, ethyloxy, propyloxy,
butyloxy, cyclopropyl, hydroxycyclopropyl, NH.sub.2, fluorine,
chlorine or bromine, and wherein the groups R.sup.3, R.sup.4 n, m
and X may have the meanings given in claim 1, optionally in the
form of the individual optical isomers, mixtures of the individual
enantiomers or racemates, in the form of the free bases or the
corresponding acid addition salts thereof with pharmacologically
acceptable acids.
9. The compound of formula 1a according to claim 1, wherein n
denotes 0 or 1; m denotes 1, 2, 3 or 4; X denotes a single bond or
one of the double-bonded groups --CH.sub.2, --CH.sub.2CH.sub.2,
--CH.sub.2--O, --O--CH.sub.2-- and --CH.sub.2; R.sup.3 denotes
hydrogen; R.sup.4 denotes OH; R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, which may be identical or different, denote hydrogen,
OR.sup.9, --C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-haloalkyl,
--C.sub.1-C.sub.4-hydroxyalkyl, --C.sub.3-C.sub.6-cycloalkyl,
--C.sub.3-C.sub.6-hydroxycycloalkyl, --CN, NO.sub.2, --COR.sup.9,
--COOR.sup.9, --CONR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10COR.sup.9, --NR.sup.10SO.sub.2R.sup.12, --SR.sup.12,
--SOR.sup.12, --SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11,
fluorine, chlorine or bromine, or two of the groups R.sup.5,
R.sup.6, R.sup.7 and R.sup.8, if they are located vicinally to the
substituting phenyl ring, together form a double-bonded group
selected from C.sub.2-C.sub.4-alkylene, C.sub.2-C.sub.4-alkenylene
and --O--C.sub.1-C.sub.4-alkylene-O-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
among methyl, methoxy, OH, fluorine, chlorine or bromine; R.sup.9
denotes hydrogen, methyl, ethyl, phenyl, naphthyl, benzyl,
naphthylmethyl or 2-phenylethyl; R.sup.10 and R.sup.11 which may be
identical or different, denote hydrogen, methyl, ethyl, phenyl,
naphthyl, naphthylmethyl, benzyl or 2-phenylethyl; R.sup.12 denotes
methyl, ethyl, phenyl, naphthyl, naphthylmethyl, benzyl or
2-phenylethyl, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids.
10. The compound of formula 1a according to claim 1, wherein n
denotes 0 or 1; m denotes 1, 2, 3 or 4; X denotes a single bond or
one of the double-bonded groups --CH.sub.2, --CH.sub.2--CH.sub.2,
--CH.sub.2--CH.sub.2-CH.sub.2, --CH.dbd.CH, --CH.sub.2--CH.dbd.CH,
--CH.sub.2--O, --CH.sub.2--CH.sub.2--O, --CH.sub.2--NH.sub.2,
--CH.sub.2--CH.sub.2--NH.sub.2--, --O--CH.sub.2-- and --CH.sub.2;
R.sup.3 denotes hydrogen; R.sup.4 denotes hydrogen, fluorine,
methyl, OH or CF.sub.3; R.sup.5 and R.sup.8 which may be identical
or different, denote hydrogen, methyl, methyloxy or fluorine;
R.sup.6 and R.sup.7 which may be identical or different, denote
hydrogen, OH, methyl, ethyl, CF.sub.3, methyloxy, ethyloxy,
propyloxy, butyloxy, cyclopropyl, hydroxycyclopropyl, NH.sub.2 or
fluorine, or R.sup.6 and R.sup.7, if they are located vicinally to
the substituting phenyl ring, together form the double-bonded group
--CH.dbd.CH--CH.dbd.CH-- wherein in each case one or 2 hydrogen
atoms may be replaced by one or two groups selected from methyl,
methoxy, OH, fluorine, chlorine and bromine, optionally in the form
of the individual optical isomers, mixtures of the individual
enantiomers or racemates, in the form of the free bases or the
corresponding acid addition salts thereof with pharmacologically
acceptable acids.
11. The compound of formula 1a according to claims 1, characterised
in that it is an enantiomer of formula R-1a, ##STR00078## wherein
the groups R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, n,
m and X may have the meanings given in claim 1.
12. A pharmaceutical composition comprising a compound of formula
1a according to claim 1 and pharmaceutically acceptable carriers or
excipients thereof.
13. A method of treating a respiratory complaints selected from
among bronchial asthma, paediatric asthma, severe asthma, acute
asthma attacks and chronic obstructive pulmonary disease,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of formula 1a
according to claim 1.
14. The pharmaceutical composition according to claim 12, which is
administered via inhalation.
Description
The present invention relates to compounds of formula 1
##STR00002## wherein the groups R.sup.1, R.sup.2, R.sup.3, R.sup.1,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, n, m and X may have the
meanings given in the claims and in the specification, and the use
thereof as pharmaceutical compositions, particularly for the
treatment of inflammatory and obstructive respiratory
complaints.
BACKGROUND TO THE INVENTION
Betamimetics (.beta.-adrenergic substances) are known from the
prior art (WO9533724; J. Med. Chem. 1976, 9, 626). For drug
treatment of diseases it is often desirable to prepare medicaments
with a longer duration of activity. As a rule, this ensures that
the concentration of the active substance in the body needed to
achieve the therapeutic effect is guaranteed for a longer period
without the need to re-administer the drug at frequent intervals.
Moreover, giving an active substance at longer time intervals
contributes to the well-being of the patient to a high degree.
It is particularly desirable to prepare a pharmaceutical
composition which can be used therapeutically by administration
once a day (single dose). The use of a drug once a day has the
advantage that the patient can become accustomed relatively quickly
to regularly taking the drug at certain times of the day.
The aim of the present invention is therefore to provide
betamimetics which are characterised by a longer duration of
activity and can thus be used to prepare pharmaceutical
compositions with a longer duration of activity. A particular aim
of the invention is to prepare betamimetics which, by virtue of
their long-lasting effect, can be used to prepare a drug for
administration once a day. A further objective of the invention is
to prepare new betamimetics which, by virtue of their long-lasting
effect, can be used to prepare a drug for administration once a day
for the treatment of inflammatory or obstructive respiratory
complaints. In addition to the objectives mentioned above a further
aim of the present invention is to prepare betamimetics which are
not only exceptionally potent but are also characterised by a high
degree of selectivity with respect to the .beta.2-adrenoceptor.
DESCRIPTION OF THE INVENTION
Surprisingly it has been found that the above-mentioned objectives
are achieved by compounds of formula 1. Accordingly, the present
invention relates to compounds of formula 1
##STR00003## wherein n denotes 0 or 1; m denotes 1, 2, 3 or 4; X
denotes a single bond or one of the double-bonded groups
C.sub.2-C.sub.6-alkenylene, --O--C.sub.1-C.sub.6-alkylene,
--NH--C.sub.1-C.sub.6-alkylene, --S--C.sub.1-C.sub.6-alkylene or
C.sub.1-C.sub.6-alkylene; R.sup.1 denotes hydrogen; R.sup.2 denotes
--C.sub.1-C.sub.4-hydroxyalkyl or halogen, or R.sup.1 and R.sup.2
together denote a double-bonded group selected from
--O--CH.sub.2--C(O)--NH, --CH.sub.2--CH.sub.2--C(O)--NH,
--CH.dbd.CH--C(O)--NH, --NH--CH.sub.2--C(O)--NH,
--S--CH.sub.2--C(O)--NH, --O--C(O)--NH, --S--C(O)--NH,
--NH--C(O)--NH, and --O--CH.sub.2--SO.sub.2-NH, wherein in each
case one or 2 hydrogen atoms may be replaced by one or two groups
selected from among --C.sub.1-C.sub.4-alkyl, OH, or halogen;
R.sup.3 and R.sup.4 which may be identical or different denote a
group selected from among hydrogen, OH, halogen,
--C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-haloalkyl,
--C.sub.1-C.sub.6-hydroxyalkyl, NH.sub.2,
NH(--C.sub.1-C.sub.4-alkyl) and N(--C.sub.1-C.sub.4-alkyl).sub.2;
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OR.sup.9, --C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.6-haloalkyl, --C.sub.1-C.sub.6-hydroxyalkyl,
--C.sub.3-C.sub.6-cycloalkyl, --C.sub.3-C.sub.6-hydroxycycloalkyl,
--CN, NO.sub.2, --COR.sup.9, --COOR.sup.9, --CONR.sup.10R.sup.11,
--NR.sup.10R.sup.11, --NR.sup.10COR.sup.9,
--NR.sup.10SO.sub.2R.sup.12, --SR.sup.12, --SOR.sup.12,
--SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11 or halogen, or two
of the groups R.sup.5, R.sup.6, R.sup.7 and R.sup.8, if they are
located vicinally to the substituting phenyl ring, together form a
double-bonded group selected from C.sub.2-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene and --O--C.sub.1-C.sub.6-alkylene-O--
wherein in each case one or 2 hydrogen atoms may be replaced by one
or two groups selected from among --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkoxy, OH, or halogen; R.sup.9 denotes hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene; R.sup.10 and
R.sup.11 which may be identical or different, denote hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene; R.sup.12 denotes
C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene, optionally in the
form of the individual optical isomers, mixtures of the individual
enantiomers or racemates, in the form of the free bases or the
corresponding acid addition salts thereof with pharmacologically
acceptable acids, and optionally in the form of the solvates or
hydrates thereof.
Preferred are compounds of general formula 1,
wherein
n denotes 0 or 1; m denotes 1, 2, 3 or 4; X denotes a single bond
or one of the double-bonded groups C.sub.2-C.sub.4-alkenylene,
--O--C.sub.1-C.sub.4-alkylene, --NH--C.sub.1-C.sub.4-alkylene,
--S--C.sub.1-C.sub.4-alkylene or C.sub.1-C.sub.4-alkylene; R.sup.1
denotes hydrogen; R.sup.2 denotes --CH.sub.2--CH.sub.2--OH,
--CH.sub.2--OH, fluorine, chlorine or bromine or R.sup.1 and
R.sup.2 together denote a double-bonded group selected from
--O--CH.sub.2--C(O)--NH, --CH.sub.2--CH.sub.2--C(O)--NH,
--CH.dbd.CH--C(O)--NH, --NH--CH.sub.2--C(O)--NH, --O--C(O)--NH,
--NH--C(O)--NH-- and --O--CH.sub.2--SO.sub.2--NH, wherein in each
case one or 2 hydrogen atoms may be replaced by one or two groups
selected from among methyl, OH, fluorine, chlorine, or bromine;
R.sup.3 and R.sup.4 which may be identical or different denote a
group selected from among hydrogen, OH, halogen,
--C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-haloalkyl,
--C.sub.1-C.sub.4-hydroxyalkyl, NH.sub.2,
NH(--C.sub.1-C.sub.4-alkyl) and N(--C.sub.1-C.sub.4-alkyl).sub.2;
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OR.sup.9, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-haloalkyl, --C.sub.1-C.sub.4-hydroxyalkyl,
--C.sub.3-C.sub.6-cycloalkyl, --C.sub.3-C.sub.6-hydroxycycloalkyl,
--CN, NO.sub.2, --COR.sup.9, --COOR.sup.9, --CONR.sup.10R.sup.11,
--NR.sup.10R.sup.11, --NR.sup.10COR.sup.9,
--NR.sup.10SO.sub.2R.sup.12, --SR.sup.12, --SOR.sup.12,
--SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11, fluorine, chlorine
or bromine, or two of the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, if they are located vicinally to the substituting phenyl
ring, together form a double-bonded group selected from
C.sub.2-C.sub.4-alkylene, C.sub.2-C.sub.4-alkenylene and
--O--C.sub.1-C.sub.4-alkylene-O-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
among methyl, methoxy, OH, fluorine, chlorine or bromine; R.sup.9
denotes hydrogen, methyl, ethyl, phenyl, naphthyl, benzyl,
naphthylmethyl or 2-phenylethyl; R.sup.10 and R.sup.11 which may be
identical or different, denote hydrogen, methyl, ethyl, phenyl,
naphthyl, naphthylmethyl, benzyl or 2-phenylethyl; R.sup.12 denotes
methyl, ethyl, phenyl, naphthyl, naphthylmethyl, benzyl or
2-phenylethyl; optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids, and optionally in
the form of the solvates or hydrates thereof.
Particularly preferred are compounds of general formula 1,
wherein
n denotes 0 or 1; m denotes 1, 2, 3 or 4; X denotes a single bond
or one of the double-bonded groups --CH.sub.2,
--CH.sub.2--CH.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2, --CH.dbd.CH,
--CH.sub.2--CH.dbd.CH, --CH.sub.2--O, --CH.sub.2--CH.sub.2--O,
--CH.sub.2--NH.sub.2, --CH.sub.2--CH.sub.2--NH.sub.2--; R.sup.1
denotes hydrogen; R.sup.2 denotes --CH.sub.2--CH.sub.2--OH,
--CH.sub.2--OH, fluorine, chlorine or bromine or R.sup.1 and
R.sup.2 together denote a double-bonded group selected from
--O--CH.sub.2--C(O)--NH, --CH.sub.2--CH.sub.2--C(O)--NH,
--CH.dbd.CH--C(O)--NH, or --O--C(O)--NH, wherein in each case one
or 2 hydrogen atoms may be replaced by one or two groups selected
from among methyl, OH, fluorine, chlorine, or bromine, preferably
methyl; R.sup.3 and R.sup.4 which may be identical or different
denote a group selected from among hydrogen, OH, fluorine,
chlorine, bromine, methyl, ethyl, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --CH.sub.2--CH.sub.2--OH, --CH.sub.2--OH, NH.sub.2,
NH(methyl) and N(methyl).sub.2; R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, which may be identical or different, denote hydrogen, OH,
methyl, ethyl, propyl, butyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2--CH.sub.2F, --CH.sub.2--CHF.sub.2, --CH.sub.2--CF.sub.3,
--CH.sub.2--CH.sub.2--OH, --CH.sub.2--OH, cyclpropyl, cyclobutyl,
cyclopentyl, HO-cyclpropyl, HO-cyclobutyl, HO-cyclopentyl, --CN,
NO.sub.2, --COphenyl, --COOmethyl, --COOethyl, --CONH.sub.2,
--CONHmethyl, --CONHphenyl, --CONHbenzyl, --CON(methyl).sub.2,
NH.sub.2, NH(methyl), N(methyl).sub.2, --NHCOmethyl, --NHCOphenyl,
--NHSO.sub.2methyl, --NHSO.sub.2phenyl,
--NHSO.sub.2-phenyl-CH.sub.3, --SO.sub.2methyl, --SO.sub.2-phenyl,
--SO.sub.2-phenyl-CH.sub.3, --SO.sub.2NH.sub.2, fluorine, chlorine
or bromine, or two of the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, if they are located vicinally to the substituting phenyl
ring, together form a double-bonded group selected from
--CH.sub.2--CH.sub.2--CH.sub.2,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2, --CH.sub.2--CH.dbd.CH,
--CH.dbd.CH--CH.dbd.CH, --O--CH.sub.2--O-- and
--O--CH.sub.2--CH.sub.2--O-- wherein in each case one or 2 hydrogen
atoms may be replaced by one or two groups selected from among
methyl, methoxy, OH or fluorine, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids, and optionally in the form of the solvates or hydrates
thereof.
Particularly preferred are compounds of formula 1, wherein X
denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single
bond or one of the double-bonded groups --O--CH.sub.2-- and
--CH.sub.2, particularly preferably --CH.sub.2, and wherein the
groups R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, n and m may have the meanings given hereinbefore,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the free
bases or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Also particularly preferred are compounds of formula 1, wherein
R.sup.1 denotes hydrogen; R.sup.2 denotes methyl, ethyl, CHF.sub.2,
CH.sub.2F, CF.sub.3, --CH.sub.2--CH.sub.2--OH, --CH.sub.2--OH,
fluorine, chlorine or bromine, or R.sup.1 and R.sup.2 together
denote a double-bonded group selected from --O--CH.sub.2--C(O)--NH,
--CH.sub.2--CH.sub.2--C(O)--NH, --CH.dbd.CH--C(O)--NH-- and
--CH.dbd.CH--CH.dbd.CH, and wherein the groups R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, n, m and X may have the
meanings given hereinbefore, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids, and optionally in the form of the solvates or hydrates
thereof.
Also particularly preferred are compounds of formula 1, wherein
R.sup.3 and R.sup.4 which may be identical or different denote a
group selected from among hydrogen, OH, fluorine, chlorine,
bromine, methyl, ethyl, CHF.sub.2, CH.sub.2F, CF.sub.3,
--CH.sub.2--CH.sub.2--OH, --CH.sub.2--OH, NH.sub.2, NHmethyl,
NHethyl, N(methyl).sub.2 and N(ethyl).sub.2, preferably selected
from among hydrogen, OH, fluorine, CH.sub.2F, CF.sub.3 and
NH.sub.2, and wherein the groups R.sup.1, R.sup.2, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, n, m and X may have the meanings given
hereinbefore, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids, and optionally in
the form of the solvates or hydrates thereof.
Also particularly preferred are compounds of formula 1, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, ethyl, propyl, butyl,
CHF.sub.2, CH.sub.2F, CF.sub.3, --CH.sub.2--CH.sub.2--OH,
--CH.sub.2--OH, methyloxy, ethyloxy, propyloxy, butyloxy,
cyclopropyl, hydroxycyclopropyl, NH.sub.2, NHmethyl,
N(methyl).sub.2, fluorine, chlorine or bromine, or two of the
groups R.sup.5, R.sup.6, R.sup.7 and R.sup.8 if they are located
vicinally to the substituted phenyl ring, together denote the
double-bonded group --CH.dbd.CH--CH.dbd.CH-- wherein in each case
one or 2 hydrogen atoms may be replaced by one or two groups
selected from among methyl, methoxy, OH, fluorine, chlorine or
bromine, and wherein the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4
n, m and X may have the meanings given hereinbefore, optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates, in the form of the free bases
or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Also particularly preferred are compounds of formula 1, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, ethyl, propyl, butyl,
CHF.sub.2, CH.sub.2F, CF.sub.3, methyloxy, ethyloxy, propyloxy,
butyloxy, cyclopropyl, hydroxycyclopropyl, NH.sub.2, fluorine,
chlorine or bromine, and wherein the groups R.sup.1, R.sup.2,
R.sup.3, R.sup.4 n, m and X may have the meanings given
hereinbefore, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids, and optionally in
the form of the solvates or hydrates thereof.
Also particularly preferred are compounds of formula 1, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, CF.sub.3, methyloxy,
ethyloxy, propyloxy, butyloxy, hydroxycyclopropyl, NH.sub.2,
fluorine or chlorine, and wherein the groups R.sup.1, R.sup.2,
R.sup.3, R.sup.4 n, m and X may have the above-mentioned meanings,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the free
bases or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Also particularly preferred are compounds of formula 1, wherein
R.sup.5 and R.sup.8 denotes hydrogen; R.sup.6 and R.sup.7 if they
are located vicinally to the substituting phenyl ring, together
denote the double-bonded group --CH.dbd.CH--CH.dbd.CH--, and
wherein the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4 n, m and X
may have the meanings given hereinbefore, optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates, in the form of the free bases or the
corresponding acid addition salts thereof with pharmacologically
acceptable acids, and optionally in the form of the solvates or
hydrates thereof.
Also particularly preferred are compounds of formula 1, wherein n
denotes 0; m denotes 2, and wherein the groups R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and X may have
the meanings given hereinbefore, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids, and optionally in the form of the solvates or hydrates
thereof.
Also particularly preferred are compounds of formula 1, wherein n
denotes 0; m denotes 3, and wherein the groups R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and X may have
the meanings given hereinbefore, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids, and optionally in the form of the solvates or hydrates
thereof.
In a preferred aspect the present invention relates to compounds of
general formula 1,
wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single
bond or one of the double-bonded groups --O--CH.sub.2-- and
--CH.sub.2, particularly preferably --CH.sub.2, R.sup.1 denotes
hydrogen and R.sup.2 denotes --CH.sub.2--OH, or R.sup.1 and R.sup.2
together denote a double-bonded group selected from
--O--CH.sub.2--C(O)--NH, --CH.sub.2--CH.sub.2--C(O)--NH,
--CH.dbd.CH--C(O)--NH, --NH--CH.sub.2--C(O)--NH,
--S--CH.sub.2--C(O)--NH, --O--C(O)--NH, --NH--C(O)--NH, and
--O--CH.sub.2--SO.sub.2--NH; R.sup.3 denotes hydrogen; R.sup.4
denotes OH, and wherein the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 may have the meanings given above, optionally in the form
of the individual optical isomers, mixtures of the individual
enantiomers or racemates, in the form of the free bases or the
corresponding acid addition salts thereof with pharmacologically
acceptable acids, and optionally in the form of the solvates or
hydrates thereof.
Preferred are compounds of general formula 1,
wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OR.sup.9, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-haloalkyl, --C.sub.1-C.sub.4-hydroxyalkyl,
--C.sub.3-C.sub.6-cycloalkyl, --C.sub.3-C.sub.6-hydroxycycloalkyl,
--CN, NO.sub.2, --COR.sup.9, --COOR.sup.9, --CONR.sup.10R.sup.11,
--NR.sup.10R.sup.11, --NR.sup.10COR.sup.9,
--NR.sup.10SO.sub.2R.sup.12, --SR.sup.12, --SOR.sup.12,
--SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11, fluorine, chlorine
or bromine, or two of the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, if they are located vicinally to the substituting phenyl
ring, together form a double-bonded group selected from
C.sub.2-C.sub.4-alkylene, C.sub.2-C.sub.4-alkenylene and
--O--C.sub.1-C.sub.4-alkylene-O-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
among methyl, methoxy, OH, fluorine, chlorine or bromine; R.sup.9
denotes hydrogen, methyl, ethyl, phenyl, naphthyl, benzyl,
naphthylmethyl or 2-phenylethyl; R.sup.10 and R.sup.11 which may be
identical or different, denote hydrogen, methyl, ethyl, phenyl,
naphthyl, naphthylmethyl, benzyl or 2-phenylethyl; R.sup.12 denotes
methyl, ethyl, phenyl, naphthyl, naphthylmethyl, benzyl or
2-phenylethyl, and wherein the groups R.sup.1, R.sup.2, R.sup.3,
R.sup.4, n, m and X may have the meanings given above, optionally
in the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates, in the form of the free bases
or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
A preferred group of compounds according to the invention are
compounds of general formula 1 wherein the groups R.sup.1 and
R.sup.2 together form the double-bonded group
--O--CH.sub.2--C(O)--NH-- and the groups R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 R.sup.8, n, m and X may have the meanings given
above.
Preferred regioisomers of this group may be represented by general
formula 1a
##STR00004##
In a preferred aspect the present invention relates to compounds of
general formula 1a,
wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single
bond or one of the double-bonded groups --O--CH.sub.2-- and
--CH.sub.2, particularly preferably --CH.sub.2, R.sup.3 denotes
hydrogen; R.sup.4 denotes OH; R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, which may be identical or different, denote hydrogen,
OR.sup.9, --C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-haloalkyl,
--C.sub.1-C.sub.4-hydroxyalkyl, --C.sub.3-C.sub.6-cycloalkyl,
--C.sub.3-C.sub.6-hydroxycycloalkyl, --CN, NO.sub.2, --COR.sup.9,
--COOR.sup.9, --CONR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10COR.sup.9, --NR.sup.10SO.sub.2R.sup.12, --SR.sup.12,
--SOR.sup.12, --SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11,
fluorine, chlorine or bromine, or two of the groups R.sup.5,
R.sup.6, R.sup.7 and R.sup.8, if they are located vicinally to the
substituting phenyl ring, together form a double-bonded group
selected from C.sub.2-C.sub.4-alkylene, C.sub.2-C.sub.4-alkenylene
and --O--C.sub.1-C.sub.4-alkylene-O-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
among methyl, methoxy, OH, fluorine, chlorine or bromine; R.sup.9
denotes hydrogen, methyl, ethyl, phenyl, naphthyl, benzyl,
naphthylmethyl or 2-phenylethyl; R.sup.10 and R.sup.11 which may be
identical or different, denote hydrogen, methyl, ethyl, phenyl,
naphthyl, naphthylmethyl, benzyl or 2-phenylethyl; R.sup.12 denotes
methyl, ethyl, phenyl, naphthyl, naphthylmethyl, benzyl or
2-phenylethyl, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids, and optionally in
the form of the solvates or hydrates thereof.
Preferred are compounds of general formula 1a, wherein n denotes 0
or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably 1; X denotes
a single bond or one of the double-bonded groups --CH.sub.2,
--CH.sub.2--CH.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2, --CH.dbd.CH,
--CH.sub.2--CH.dbd.CH, --CH.sub.2--O, --CH.sub.2--CH.sub.2--O,
--CH.sub.2--NH.sub.2, --CH.sub.2--CH.sub.2-NH.sub.2--; R.sup.3
denotes hydrogen; R.sup.4 denotes hydrogen, fluorine, methyl, OH or
CF.sub.3, preferably OH; R.sup.5 and R.sup.8 which may be identical
or different, denote hydrogen, methyl, methyloxy or fluorine;
R.sup.6 and R.sup.7 which may be identical or different, denote
hydrogen, OH, methyl, ethyl, CF.sub.3, methyloxy, ethyloxy,
propyloxy, butyloxy, cyclopropyl, hydroxycyclopropyl, NH.sub.2 or
fluorine, or R.sup.6 and R.sup.7, if they are located vicinally to
the substituting phenyl ring, together form the double-bonded group
--CH.dbd.CH--CH.dbd.CH-- wherein in each case one or 2 hydrogen
atoms may be replaced by one or two groups selected from among
methyl, methoxy, OH, fluorine, chlorine and bromine, optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates, in the form of the free bases
or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Preferred are compounds of general formula 1a, wherein n denotes 0
or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably 1; X denotes
a single bond or one of the double-bonded groups --CH.sub.2,
--CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single bond or one
of the double-bonded groups --O--CH.sub.2-- and --CH.sub.2,
particularly preferably --CH.sub.2, R.sup.3 denotes hydrogen;
R.sup.4 denotes OH; R.sup.5 and R.sup.8 which may be identical or
different, denote hydrogen, methyl, methyloxy or fluorine; R.sup.6
and R.sup.7 which may be identical or different, denote hydrogen,
OH, methyl, CF.sub.3, methyloxy, ethyloxy, propyloxy, butyloxy,
hydroxycyclopropyl, NH.sub.2 or fluorine, or R.sup.6 and R.sup.7,
if they are located vicinally to the substituting phenyl ring,
together form the double-bonded group --CH.dbd.CH--CH.dbd.CH,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the free
bases or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Particularly preferred are compounds of general formula a, wherein
R.sup.4 denotes OH; R.sup.5, R.sup.6 and R.sup.8 which may be
identical or different, denote hydrogen or methyl, preferably
hydrogen; R.sup.7 denotes hydrogen, OH, methyl, CF.sub.3,
methyloxy, ethyloxy, propyloxy or butyloxy, preferably OH,
methyloxy, ethyloxy, propyloxy or butyloxy, and n, m, X and R.sup.3
may have the meanings given above, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids, and optionally in the form of the solvates or hydrates
thereof.
A preferred group of compounds according to the invention are
compounds of general formula 1 wherein the groups R.sup.1 and
R.sup.2 together form the double-bonded group
--CH.dbd.CH--C(O)--NH-- and the groups R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, n, m and X may have the meanings given
above.
Preferred regioisomers of this group may be represented by general
formula 1b
##STR00005##
In a preferred aspect the present invention relates to compounds of
general formula 1b,
wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2--CH.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2,
--CH.dbd.CH, --CH.sub.2--CH.dbd.CH, --CH.sub.2--O,
--CH.sub.2--CH.sub.2--O, --CH.sub.2--NH.sub.2,
--CH.sub.2--CH.sub.2--NH.sub.2--; R.sup.3 denotes hydrogen; R.sup.4
denotes hydrogen, fluorine, methyl, OH or CF.sub.3, preferably OH;
R.sup.5 and R.sup.8 which may be identical or different, denote
hydrogen, methyl, methyloxy or fluorine; R.sup.6 and R.sup.7 which
may be identical or different, denote hydrogen, OH, methyl, ethyl,
CF.sub.3, methyloxy, ethyloxy, propyloxy, butyloxy, cyclopropyl,
hydroxycyclopropyl, NH.sub.2 or fluorine, or R.sup.6 and R.sup.7,
if they are located vicinally to the substituting phenyl ring,
together form the double-bonded group --CH.dbd.CH--CH.dbd.CH--
wherein in each case one or 2 hydrogen atoms may be replaced by one
or two groups selected from among methyl, methoxy, OH, fluorine,
chlorine and bromine, optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates, in the form of the free bases or the corresponding acid
addition salts thereof with pharmacologically acceptable acids, and
optionally in the form of the solvates or hydrates thereof.
Preferred are compounds of general formula 1b, wherein n denotes 0
or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably 1; X denotes
a single bond or one of the double-bonded groups --CH.sub.2,
--CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single bond or one
of the double-bonded groups --O--CH.sub.2-- and --CH.sub.2,
particularly preferably --CH.sub.2, R.sup.3 denotes hydrogen;
R.sup.4 denotes OH; R.sup.5 and R.sup.8 which may be identical or
different, denote hydrogen, methyl, methyloxy or fluorine; R.sup.6
and R.sup.7 which may be identical or different, denote hydrogen,
OH, methyl, CF.sub.3, methyloxy, ethyloxy, propyloxy, butyloxy,
hydroxycyclopropyl, NH.sub.2 or fluorine, or R.sup.6 and R.sup.7,
if they are located vicinally to the substituting phenyl ring,
together form the double-bonded group --CH.dbd.CH--CH.dbd.CH,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the free
bases or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Particularly preferred are compounds of general formula 1b, wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes the double-bonded group --CH.sub.2--; R.sup.3 denotes
hydrogen; R.sup.4 denotes OH; R.sup.5, R.sup.6 and R.sup.8 which
may be identical or different, denote hydrogen or methyl,
preferably hydrogen; R.sup.7 denotes hydrogen, OH, methyl,
CF.sub.3, methyloxy or ethyloxy, preferably OH, CF.sub.3 or
methyloxy, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates, in
the form of the free bases or the corresponding acid addition salts
thereof with pharmacologically acceptable acids, and optionally in
the form of the solvates or hydrates thereof.
A preferred group of compounds according to the invention are
compounds of general formula 1 wherein R.sup.1 denotes hydrogen,
R.sup.2 denotes chlorine, R.sup.3 denotes NH.sub.2 and R.sup.4
denotes chlorine and the groups R.sup.5, R.sup.6, R.sup.7, R.sup.8,
n, m and X may have the meanings given above. Preferred
regioisomers of this group may be represented by general formula
1c
##STR00006##
In a preferred aspect the present invention relates to compounds of
general formula 1c,
wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2--CH.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2,
--CH.dbd.CH, --CH.sub.2--CH.dbd.CH, --CH.sub.2--O,
--CH.sub.2--CH.sub.2--O, --CH.sub.2--NH.sub.2,
--CH.sub.2--CH.sub.2--NH.sub.2--; R.sup.5 and R.sup.8 which may be
identical or different, denote hydrogen, methyl, methyloxy or
fluorine; R.sup.6 and R.sup.7 which may be identical or different,
denote hydrogen, OH, methyl, ethyl, CF.sub.3, methyloxy, ethyloxy,
propyloxy, butyloxy, cyclopropyl, hydroxycyclopropyl, NH.sub.2 or
fluorine, or R.sup.6 and R.sup.7, if they are located vicinally to
the substituting phenyl ring, together form the double-bonded group
--CH.dbd.CH--CH.dbd.CH-- wherein in each case one or 2 hydrogen
atoms may be replaced by one or two groups selected from among
methyl, methoxy, OH, fluorine, chlorine and bromine, optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates, in the form of the free bases
or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Preferred are compounds of general formula 1c, wherein n denotes 0
or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably 1; X denotes
a single bond or one of the double-bonded groups --CH.sub.2,
--CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single bond or one
of the double-bonded groups --O--CH.sub.2-- and --CH.sub.2,
particularly preferably --CH.sub.2, R.sup.5 and R.sup.8 denotes
hydrogen; R.sup.6 and R.sup.7 which may be identical or different,
denote hydrogen, OH, methyl, CF.sub.3, methyloxy or ethyloxy,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the free
bases or the corresponding acid addition salts thereof with
pharmacologically acceptable acids, and optionally in the form of
the solvates or hydrates thereof.
Particularly preferred are compounds of general formula 1c, wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes the double-bonded group --CH.sub.2--; R.sup.5, R.sup.6
and R.sup.8 which may be identical or different, denote hydrogen or
methyl, preferably hydrogen; R.sup.7 denotes hydrogen, OH,
methyloxy or ethyloxy, optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates, in the form of the free bases or the corresponding acid
addition salts thereof with pharmacologically acceptable acids, and
optionally in the form of the solvates or hydrates thereof.
A preferred group of compounds according to the invention are
compounds of general formula 1 wherein R.sup.1 denotes hydrogen,
R.sup.2 denotes hydroxymethyl and R.sup.3 denotes OH and the groups
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, n, m and X may have
the meanings given above.
Preferred regioisomers of this group may be represented by general
formula 1d
##STR00007##
In a preferred aspect the present invention relates to compounds of
general formula 1d,
wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2--CH.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2,
--CH.dbd.CH, --CH.sub.2--CH.dbd.CH, --CH.sub.2--O,
--CH.sub.2--CH.sub.2--O, --CH.sub.2--NH.sub.2,
--CH.sub.2--CH.sub.2--NH.sub.2--; R.sup.4 denotes hydrogen,
fluorine, methyl, OH or CF.sub.3, preferably hydrogen; R.sup.5 and
R.sup.8 which may be identical or different, denote hydrogen,
methyl, methyloxy or fluorine; R.sup.6 and R.sup.7 which may be
identical or different, denote hydrogen, OH, methyl, ethyl,
CF.sub.3, methyloxy, ethyloxy, propyloxy, butyloxy, cyclopropyl,
hydroxycyclopropyl, NH.sub.2 or fluorine, or R.sup.6 and R.sup.7,
if they are located vicinally to the substituting phenyl ring,
together form the double-bonded group --CH.dbd.CH--CH.dbd.CH--
wherein in each case one or 2 hydrogen atoms may be replaced by one
or two groups selected from among methyl, methoxy, OH, fluorine,
chlorine and bromine, optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates, in the form of the free bases or the corresponding acid
addition salts thereof with pharmacologically acceptable acids, and
optionally in the form of the solvates or hydrates thereof.
Preferred are compounds of general formula 1 d, wherein n denotes 0
or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably 1; X denotes
a single bond or one of the double-bonded groups --CH.sub.2,
--CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single bond or one
of the double-bonded groups --O--CH.sub.2-- and --CH.sub.2,
particularly preferably --CH.sub.2, R.sup.4 denotes hydrogen;
R.sup.5 and R.sup.8 which may be identical or different, denote
hydrogen, methyl, methyloxy or fluorine, preferably hydrogen;
R.sup.6 and R.sup.7 which may be identical or different, denote
hydrogen, OH, methyl, CF.sub.3, methyloxy, ethyloxy, propyloxy,
butyloxy, NH.sub.2 or fluorine, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids, and optionally in the form of the solvates or hydrates
thereof.
Particularly preferred are compounds of general formula 1d, wherein
n denotes 0 or 1, preferably 0; m denotes 1, 2, 3 or 4, preferably
1; X denotes the double-bonded group --CH.sub.2--; R.sup.4 denotes
hydrogen; R.sup.5, R.sup.6 and R.sup.8 which may be identical or
different, denote hydrogen or methyl, preferably hydrogen; R.sup.7
denotes hydrogen, OH, methyl, CF.sub.3, methyloxy or ethyloxy,
preferably OH, CF.sub.3 or methyloxy, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates, in the form of the free bases or the corresponding
acid addition salts thereof with pharmacologically acceptable
acids, and optionally in the form of the solvates or hydrates
thereof.
Particularly preferred compounds of formula 1 are selected from
among:
5-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-4-
H-benzo[1,4]oxazin-3-one;
8-[2-(1-benzyl-cyclopropylamino)-1-hydroxy-ethyl]-5-hydroxy-4H-benzo[1,4]-
oxazin-3-one;
8-{2-[1-(2,6-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydrox-
y-4H-benzo[1,4]oxazin-3-one;
8-{2-[1-(3,4-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydrox-
y-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(3-methyl-benzyl)-cyclopropylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(2-trifluoromethyl-benzyl)-cyclopropylamino]--
ethyl}-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-(1-hydroxy-2-{1-[4-(1-hydroxy-cyclopropyl)-benzyl]-cyclopropy-
lamino}-ethyl)-4H-benzo[1,4]oxazin-3-one;
8-{2-[1-(3,5-difluoro-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydrox-
y-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-[1-hydroxy-2-(1-phenoxymethyl-cyclopropylamino)-ethyl]-4H-ben-
zo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopropylamino]--
ethyl}-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(2-methoxy-benzyl)-cyclopropylamino]-ethyl}-4-
H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(2-methyl-benzyl)-cyclopropylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one;
8-{2-[1-(2,6-dimethyl-phenoxymethyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-
-hydroxy-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-[1-hydroxy-2-(1-naphthalen-2-ylmethyl-cyclopropylamino)-ethyl-
]-4H-benzo[1,4]oxazin-3-one;
8-{2-[1-(2,4-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydrox-
y-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(2,3,5,6-tetramethyl-benzyl)-cyclopropylamino-
]-ethyl}-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-(1-hydroxy-2-{1-[2-(4-methoxy-phenyl)-ethyl]-cyclopropylamino-
}-ethyl)-4H-benzo[1,4]oxazin-3-one;
8-{2-[1-(2,6-difluoro-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydrox-
y-4H-benzo[1,4]oxazin-3-one;
8-{2-[1-(4-amino-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-4H--
benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(4-hydroxy-benzyl)-cyclopropylamino]-ethyl}-4-
H-benzo[1,4]oxazin-3-one;
8-{2-[1-(3,4-dimethoxy-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydro-
xy-4H-benzo[1,4]oxazin-3-one;
8-{2-[1-(4-ethoxy-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-4H-
-benzo[1,4]oxazin-3-one;
8-{2-[1-(4-butoxy-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-4H-
-benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(2,4,6-trimethyl-benzyl)-cyclopropylamino]-et-
hyl}-4H-benzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[(1-phenyl-cyclopropylmethyl)-amino]-ethyl}-4H-b-
enzo[1,4]oxazin-3-one;
5-hydroxy-8-{1-hydroxy-2-[1-(2-naphthalen-2-yl-ethyl)-cyclopropylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one;
2-hydroxymethyl-4-{1-hydroxy-2-[(1-phenyl-cyclopropylmethyl)-amino]-ethyl-
}-phenol;
4-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-2--
hydroxymethyl-phenol;
4-[2-(1-benzyl-cyclopropylamino)-1-hydroxy-ethyl]-2-hydroxymethyl-phenol;
4-{2-[1-(2,6-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-2-hydrox-
ymethyl-phenol;
6-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-4-
H-benzo[1,4]oxazin-3-one;
6-hydroxy-8-{1-hydroxy-2-[1-(4-hydroxy-benzyl)-cyclopropylamino]-ethyl}-4-
H-benzo[1,4]oxazin-3-one;
6-hydroxy-8-{1-hydroxy-2-[(1-phenyl-cyclopropylmethyl)-amino]-ethyl}-4H-b-
enzo[1,4]oxazin-3-one;
8-{2-[1-(2,6-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-6-hydrox-
y-4H-benzo[1,4]oxazin-3-one;
8-{2-[1-(4-chloro-phenoxymethyl)-cyclopropylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one;
1-(4-amino-3,5-dichloro-phenyl)-2-[(1-phenyl-cyclopropylmethyl)-amino}-et-
hanol;
1-(4-amino-3,5-dichloro-phenyl)-2-[1-(2,6-dimethyl-benzyl)-cyclopro-
pylamino]-ethanol;
1-(4-amino-3,5-dichloro-phenyl)-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-
-ethanol;
1-(4-amino-3,5-dichloro-phenyl)-2-(1-benzyl-cyclopropylamino)-et-
hanol;
8-hydroxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-et-
hyl}-1H-quinolin-2-one and
8-hydroxy-5-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopropylamino]--
ethyl}-1H-quinolin-2-one, optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates, in the form of the free bases or the corresponding acid
addition salts thereof with pharmacologically acceptable acids, and
optionally in the form of the solvates or hydrates thereof.
The compounds of formula 1 may optionally be used in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates. Most preferably they are used in the form
of the enantiomerically pure compounds, wherein the asymmetric
carbon centre "--CH(OH)--" benzylic to the phenyl ring in the
compounds of formula 1 is in the R-configuration. The particularly
preferred R-enantiomers of the compounds of general formula 1 may
be represented by general formula R-1,
##STR00008## wherein the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, n, m and X may have the
meanings given above.
By acid addition salts with pharmacologically acceptable acids are
meant for example salts selected from the group comprising the
hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrobenzoate, hydrocitrate, hydroffumarate,
hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate, preferably the hydrochloride,
hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
Halogen within the scope of the present invention denotes fluorine,
chlorine, bromine or iodine. Unless stated otherwise, fluorine and
chlorine are the preferred halogens, while fluorine is generally
preferred.
Unless otherwise stated, the alkyl groups (alkyl) are
straight-chained or branched alkyl groups having 1 to 6, preferably
1 to 4 carbon atoms. The following are mentioned by way of example:
methyl, ethyl, propyl or butyl. In some cases the abbreviations Me,
Et, Prop or Bu are used to denote the groups methyl, ethyl, propyl
or butyl. Unless otherwise stated, the definitions propyl and butyl
include all the possible isomeric forms of the groups in question.
Thus, for example, propyl includes n-propyl and iso-propyl, butyl
includes iso-butyl, sec.butyl and tert.-butyl, etc.
Unless otherwise stated, the alkylene groups (alkylene) are
branched and unbranched alkylene groups with 1 to 6, preferably 1
to 4 carbon atoms. The following are mentioned by way of example:
methylene, ethylene, propylene or butylene. Unless otherwise
stated, the definitions propylene and butylene include all the
possible isomeric forms of the groups in question.
Unless otherwise stated, the alkenylene groups (alkenylene) are
branched and unbranched alkenylene groups with 1 to 6, preferably 1
to 4 carbon atoms. The following are mentioned by way of example:
ethenylene, propenylene or butenylene.
Unless otherwise stated, the cycloalkyl groups (cycloalkyl) are
cyclic alkyl groups with 3 to 6. The following are mentioned by way
of example: cyclopropyl, cyclobutanyl, cyclopentyl or cyclohexyl.
Hydroxyalkyl groups within the scope of the present invention are
cycloalkyl groups wherein one or more, preferably one hydrogen atom
is substituted by hydroxy.
Unless otherwise stated, the alkyloxy groups (O-alkyl) are branched
and unbranched alkyl groups with 1 to 6, preferably 1 to 4 carbon
atoms which are linked via an oxygen atom. The following are
mentioned by way of example: methyloxy, ethyloxy, propyloxy or
butyloxy. In some cases the abbreviations --OMe, --OEt, --OProp or
--OBu may be used to denote the methyloxy, ethyloxy, propyloxy or
butyloxy groups. Unless otherwise stated, the definitions propyloxy
and butyloxy include all the possible isomeric forms of the groups
in question. Thus, for example, propyloxy includes n-propyloxy and
iso-propyloxy, butyloxy includes iso-butyloxy, sec.butyloxy and
tert.-butyloxy, etc. In some cases the term alkoxy may be used
instead of alkyloxy within the scope of the present invention. The
groups methyloxy, ethyloxy, propyloxy or butyloxy may therefore
also be referred to by the names methoxy, ethoxy, propoxy or
butoxy.
Unless otherwise stated, the haloalkylene groups (haloalkyl) are
branched and unbranched alkyl groups with 1 to 6 carbon atoms,
wherein one or more hydrogen atoms are replaced by halogen atoms,
preferably by fluorine. Examples include: CHF.sub.2, CF.sub.3,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3.
Unless otherwise stated, the aryl groups are aromatic ring systems
with 6 to 10 carbon atoms. Preferred aryl groups are phenyl and
naphthyl, while phenyl is particularly preferred according to the
invention.
Unless otherwise stated, the heterocyclic groups (heterocycles) are
aromatic or non-aromatic ring systems with 2 to 5 carbon atoms and
1, 2 or 3 atoms selected from the group O, S or N, preferably N.
Particularly preferred heterocycles are piperidine, piperazine,
morpholine, pyrolidine, pyrrole, imidazole, triazole, pyridine,
pyrimidine, thiophene, tetrahydrofuran or furan.
The compounds according to the invention may be prepared
analogously to methods already known in the art. Suitable methods
of preparation are known for example from WO95/33724, which is
hereby incorporated in its entirety by reference.
Essential components for preparing the compounds of general formula
1 according to the invention are particularly the cycloalkylamines
of formula 2,
##STR00009## wherein the groups R.sup.5, R.sup.6, R.sup.7, R.sup.8,
n, m and X may have the meanings given above.
The compounds of formula 2 may be prepared analogously to methods
known in the art (Bertus et al., J. Org. Chem. 2002, 67,
3965-3968).
The compounds of formula 2 are not known in the art. Accordingly,
in another aspect, the present invention relates to the compounds
of formula 2,
wherein
n denotes 0 or 1; m denotes 1; X denotes a single bond or one of
the double-bonded groups --O, --NH, --S,
C.sub.2-C.sub.6-alkenylene, --O--C.sub.1-C.sub.6-alkylene,
--NH--C.sub.1-C.sub.6-alkylene, --S--C.sub.1-C.sub.6-alkylene or
C.sub.1-C.sub.6-alkylene; R.sup.5, R.sup.6, R.sup.7 and R.sup.8,
which may be identical or different, denote hydrogen, OR.sup.9,
--C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-haloalkyl,
--C.sub.1-C.sub.6-hydroxyalkyl, --C.sub.3-C.sub.6-cycloalkyl,
--C.sub.3-C.sub.6-hydroxycycloalkyl, --CN, NO.sub.2, --COR.sup.9,
--COOR.sup.9, --CONR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10COR.sup.9, --NR.sup.10SO.sub.2R.sup.12, --SR.sup.12,
--SOR.sup.12, --SO.sub.2R.sup.12, --SO.sub.2NR.sup.10R.sup.11 or
halogen, or two of the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, if they are located vicinally to the substituting phenyl
ring, together form a double-bonded group selected from
C.sub.2-C.sub.6-alkylene, C.sub.2-C.sub.6-alkenylene and
--O--C.sub.1-C.sub.6-alkylene-O-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
among --C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkoxy, OH, or
halogen; R.sup.9 denotes hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene; R.sup.10 and
R.sup.11 which may be identical or different, denote hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene; R.sup.12
C.sub.1-C.sub.4-alkyl, C.sub.6-C.sub.10-aryl or
C.sub.6-C.sub.10-aryl-C.sub.1-C.sub.4-alkylene; optionally in the
form of the individual optical isomers, mixtures of the individual
enantiomers or racemates.
Preferred are compounds of general formula 2,
wherein
n denotes 0 or 1, preferably 0; m denotes 1; X denotes a single
bond or one of the double-bonded groups C.sub.2-C.sub.4-alkenylene,
--O--C.sub.1-C.sub.4-alkylene, --NH--C.sub.1-C.sub.4-alkylene,
--S--C.sub.1-C.sub.4-alkylene or C.sub.1-C.sub.4-alkylene; R.sup.5,
R.sup.6, R.sup.7 and R.sup.8, which may be identical or different,
denote hydrogen, OR.sup.9, --C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-haloalkyl, --C.sub.1-C.sub.4-hydroxyalkyl,
--C.sub.3-C.sub.6-cycloalkyl, --C.sub.3-C.sub.6-hydroxycycloalkyl,
--CN, NO.sub.2, --COR.sup.9, --COOR.sup.9, --CONR.sup.10R.sup.11,
--NR.sup.11, --NR.sup.10COR.sup.9, --NR.sup.10SO.sub.2R.sup.12,
--SR.sup.12, --SOR.sup.12, --SO.sub.2R.sup.12,
--SO.sub.2NR.sup.10R.sup.11, fluorine, chlorine or bromine, or two
of the groups R.sup.5, R.sup.6, R.sup.7 and R.sup.8, if they are
located vicinally to the substituting phenyl ring, together form a
double-bonded group selected from C.sub.2-C.sub.4-alkylene,
C.sub.2-C.sub.4-alkenylene and --O--C.sub.1-C.sub.4-alkylene-O--
wherein in each case one or 2 hydrogen atoms may be replaced by one
or two groups selected from among methyl, methoxy, OH, fluorine,
chlorine or bromine; R.sup.9 denotes hydrogen, methyl, ethyl,
phenyl, naphthyl, benzyl, naphthylmethyl or 2-phenylethyl; R.sup.10
and R.sup.11 which may be identical or different, denote hydrogen,
methyl, ethyl, phenyl, naphthyl, naphthylmethyl, benzyl or
2-phenylethyl; R.sup.12 denotes methyl, ethyl, phenyl, naphthyl,
naphthylmethyl, benzyl or 2-phenylethyl; optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates.
Particularly preferred are compounds of general formula 2,
wherein
n denotes 0 or 1, preferably 1; m denotes 1; X denotes a single
bond or one of the double-bonded groups --CH.sub.2,
--CH.sub.2--CH.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2, --CH.dbd.CH,
--CH.sub.2--CH.dbd.CH, --CH.sub.2--O, --CH.sub.2--CH.sub.2--O,
--CH.sub.2--O, --CH.sub.2--CH.sub.2--O, --CH.sub.2--NH.sub.2,
--CH.sub.2--CH.sub.2--NH.sub.2--; R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, which may be identical or different, denote hydrogen, OH,
methyl, ethyl, propyl, butyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2--CH.sub.2F, --CH.sub.2--CHF.sub.2, --CH.sub.2--CF.sub.3,
--CH.sub.2--CH.sub.2--OH, --CH.sub.2--OH, cyclopropyl, cyclobutyl,
cyclopentyl, HO-cyclopropyl, HO-cyclobutyl, HO-cyclopentyl, --CN,
NO.sub.2, --COphenyl, --COOmethyl, --COOethyl, --CONH.sub.2,
--CONHmethyl, --CONHphenyl, --CONHbenzyl, --CON(methyl).sub.2,
NH.sub.2, NH(methyl), N(methyl).sub.2, --NHCOmethyl, --NHCOphenyl,
--NHSO.sub.2methyl, --NHSO.sub.2phenyl,
--NHSO.sub.2-phenyl-CH.sub.3, --SO.sub.2methyl, --SO.sub.2-phenyl,
--SO.sub.2-phenyl-CH.sub.3, --SO.sub.2NH.sub.2, fluorine, chlorine
or bromine, or two of the groups R.sup.5, R.sup.6, R.sup.7 and
R.sup.8, if they are located vicinally to the substituting phenyl
ring, together form a double-bonded group selected from
--CH.sub.2--CH.sub.2--CH.sub.2,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2, --CH.sub.2--CH.dbd.CH,
--CH.dbd.CH--CH.dbd.CH, --O--CH.sub.2--O-- and
--O--CH.sub.2--CH.sub.2--O-- wherein in each case one or 2 hydrogen
atoms may be replaced by one or two groups selected from among
methyl, methoxy, OH or fluorine, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates.
Particularly preferred are compounds of formula 2, wherein X
denotes a single bond or one of the double-bonded groups
--CH.sub.2, --CH.sub.2CH.sub.2, --CH.sub.2--O, preferably a single
bond or one of the double-bonded groups --O--CH.sub.2-- and
--CH.sub.2, particularly preferably --CH.sub.2, and wherein the
groups R.sup.5, R.sup.6, R.sup.7, R.sup.8, n and m may have the
meanings given hereinbefore, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates.
Also particularly preferred are compounds of formula 2, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, ethyl, propyl, butyl,
CHF.sub.2, CH.sub.2F, CF.sub.3, --CH.sub.2--CH.sub.2--OH,
--CH.sub.2--OH, methyloxy, ethyloxy, propyloxy, butyloxy,
cyclopropyl, hydroxycyclopropyl, NH.sub.2, NHmethyl,
N(methyl).sub.2, fluorine, chlorine or bromine, or two of the
groups R.sup.5, R.sup.6, R.sup.7 and R.sup.8, if they are located
vicinally to the substituting phenyl ring, denote the double-bonded
group --CH.dbd.CH--CH.dbd.CH-- wherein in each case one or 2
hydrogen atoms may be replaced by one or two groups selected from
among methyl, methoxy, OH, fluorine, chlorine or bromine, and
wherein the groups n, m and X may have the meanings given
hereinbefore, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates.
Also particularly preferred are compounds of formula 2, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, ethyl, propyl, butyl,
CHF.sub.2, CH.sub.2F, CF.sub.3, methyloxy, ethyloxy, propyloxy,
butyloxy, cyclopropyl, hydroxycyclopropyl, NH.sub.2, fluorine,
chlorine or bromine, and wherein the groups n, m and X may have the
meanings given hereinbefore, optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates.
Also particularly preferred are compounds of formula 2, wherein
R.sup.5, R.sup.6, R.sup.7 and R.sup.8, which may be identical or
different, denote hydrogen, OH, methyl, CF.sub.3, methyloxy,
ethyloxy, propyloxy, butyloxy, hydroxycyclopropyl, NH.sub.2,
fluorine or chlorine, and wherein the groups n, m and X may have
the meanings given above, optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates.
Also particularly preferred are compounds of formula 2, wherein
R.sup.5 and R.sup.8 denotes hydrogen; R.sup.6 and R.sup.7, if they
are located vicinally to the substituting phenyl ring, together
denote the double-bonded group --CH.dbd.CH--CH.dbd.CH--, and
wherein the groups n, m and X may have the meanings given
hereinbefore, optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates.
In a preferred aspect the present invention also relates to
compounds of general formula 2,
wherein
n denotes 0 or 1, preferably 0; m denotes 1; X denotes a single
bond or one of the double-bonded groups --CH.sub.2,
--CH.sub.2--CH.sub.2, --CH.sub.2--CH.sub.2--CH.sub.2, --CH.dbd.CH,
--CH.sub.2--CH.dbd.CH, --CH.sub.2--O, --CH.sub.2--CH.sub.2--O,
--CH.sub.2--NH.sub.2, --CH.sub.2--CH.sub.2--NH.sub.2--; R.sup.5 and
R.sup.8 which may be identical or different, denote hydrogen,
methyl, methyloxy or fluorine; R.sup.6 and R.sup.7 which may be
identical or different, denote hydrogen, OH, methyl, ethyl,
CF.sub.3, methyloxy, ethyloxy, propyloxy, butyloxy, cyclopropyl,
hydroxycyclopropyl, NH.sub.2 or fluorine, or R.sup.6 and R.sup.7,
if they are located vicinally to the substituting phenyl ring,
together form the double-bonded group --CH.dbd.CH--CH.dbd.CH--
wherein in each case one or 2 hydrogen atoms may be replaced by one
or two groups selected from among methyl, methoxy, OH, fluorine,
chlorine and bromine, optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates.
Preferred are compounds of general formula 2, wherein n denotes 0
or 1, preferably 0; m denotes 1; X denotes a single bond or one of
the double-bonded groups --CH.sub.2, --CH.sub.2CH.sub.2,
--CH.sub.2--O, preferably a single bond or one of the double-bonded
groups --O--CH.sub.2-- and --CH.sub.2, particularly preferably
--CH.sub.2, R.sup.5 and R.sup.8 which may be identical or
different, denote hydrogen, methyl, methyloxy or fluorine; R.sup.6
and R.sup.7 which may be identical or different, denote hydrogen,
OH, methyl, CF.sub.3, methyloxy, ethyloxy, propyloxy, butyloxy,
hydroxycyclopropyl, NH.sub.2 or fluorine, or R.sup.6 and R.sup.7,
if they are located vicinally to the substituting phenyl ring,
together form the double-bonded group --CH.dbd.CH--CH.dbd.CH,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates.
Particularly preferred are compounds of general formula 2, wherein
R.sup.5, R.sup.6 and R.sup.8 which may be identical or different,
denote hydrogen or methyl, preferably hydrogen; R.sup.7 denotes
hydrogen, OH, methyl, CF.sub.3, methyloxy, ethyloxy, propyloxy or
butyloxy, preferably OH, methyloxy, ethyloxy, propyloxy or
butyloxy, and n, m and X may have the meanings given above,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates.
Particularly preferred compounds of formula 2 are selected from
among:
##STR00010## ##STR00011##
The examples of synthesis described hereinafter serve to illustrate
possible methods of synthesising new compounds according to the
invention. However, they are intended only as examples of
procedures as an illustration of the invention without restricting
the invention to the subject-matter described by way of
example.
Synthesis of the Intermediates:
General Method 1:
1 equivalent titanium tetraisopropoxide is added dropwise at -15 to
-25.degree. C. to a solution of 1 equivalent (typically
approximately 30 mmol) of phenylacetonitrile in 150 mL diethyl
ether. The mixture is stirred for 30 minutes at ambient temperature
and then combined with 2 equivalents of boron trifluoride diethyl
etherate, while the reaction mixture is cooled such that the
temperature does not exceed 20.degree. C. The mixture is stirred
for 30 minutes, 120 mL of 1 M sodium hydroxide solution are slowly
added dropwise and the mixture is stirred for a further 60 minutes.
The aqueous phase is separated off and extracted with diethyl
ether. Then the combined ether phases are washed with sodium
sulphite solution and extracted with 0.5 molar hydrochloric acid.
The hydrochloric acid fraction containing the product is made
alkaline with sodium hydroxide solution and extracted with
dichloromethane. The organic phases are dried with sodium sulphate
and evaporated down. The residue is purified by chromatography on a
silica gel column (dichloromethane/methanol/ammonia gradient).
1-(2,3,5,6-tetramethyl-benzyl)-cyclopropylamine
Prepared from 5.0 g (29 mmol)
(2,3,5,6-tetramethyl-phenyl)-acetonitrile according to general
method 1.
Yield: 2.5 g (43%); mass spectroscopy: [M+H].sup.+=204.
1-(3,4-dimethoxy-benzyl)-cyclopropylamine
The compound is prepared according to general method 1 from 5.2 g
(29 mmol) (3,4-dimethoxy-phenyl)-acetonitrile. Yield: 1.6 g (27%);
mass spectroscopy: [M+H].sup.+=208.
1-(4-butoxy-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.6 g (29 mmol)
(4-butoxy-phenyl)-acetonitrile.
Yield: 2.7 g (43%); mass spectroscopy: [M+H].sup.+=220.
1-(4-ethoxy-benzyl)-cyclopropylamine
Prepared according to general method 1 from 4.7 g (29 mmol)
(4-ethoxy-phenyl)-acetonitrile.
Yield: 1.9 g (35%); mass spectroscopy: [M+H].sup.+=192.
1-(2,6-difluoro-benzyl)-cycloprolpylamine
Prepared analogously to general method 1 from 5.0 g (33 mmol)
(2,6-difluoro-phenyl)-acetonitrile. Yield: 3.0 g (50%); mass
spectroscopy: [M+H].sup.+=184.
1-(4-chloro-benzyl)-cyclopropylamine
Prepared according to general method 1 from 4.5 g (29 mmol)
(4-chloro-phenyl)-acetonitrile.
Yield: 2.0 g (38%); mass spectroscopy: [M+H].sup.+=182/4.
1-[4-(1-amino-cyclopropylmethyl)-phenyl]-cyclopropanol
4.0 g (21 mmol) ethyl 4-cyanomethyl-benzoate are reacted and worked
up analogously to general method 1. Yield: 0.6 g (14%); mass
spectroscopy: [M+H].sup.+=204.
1-(3,5-difluoro-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.0 g (32 mmol)
(3,5-difluoro-phenyl)-acetonitrile. Yield: 2.7 g (47%); mass
spectroscopy: [M+H].sup.+=184.
1-(4-trifluoromethyl-benzyl)-cyclopropylamine
The compound is prepared according to general method 1 from 5.0 g
(26 mmol) (4-trifluoromethyl-phenyl)-acetonitrile. Yield: 3.1 g
(54%); mass spectroscopy: [M+H].sup.+=216.
1-(2,4-dichloro-benzyl)-cyclopropylamine
Prepared according to general method 1 from 6.3 g (33 mmol)
(2,4-dichloro-phenyl)-acetonitrile. Yield: 3.1 g (43%); mass
spectroscopy: [M+H].sup.+=216/218/220.
1-(2-chloro-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.1 g (34 mmol)
(2-chloro-phenyl)-acetonitrile.
Yield: 2.3 g (38%); mass spectroscopy: [M+H].sup.+=182/184.
1-(4-trifluoromethoxy-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.0 g (25 mmol)
(4-trifluoromethoxy-phenyl)-acetonitrile. Yield: 2.9 g (51%); mass
spectroscopy: [M+H].sup.+=232.
1-(2-methoxy-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.0 g (34 mmol)
(2-methoxy-phenyl)-acetonitrile. Yield: 1.7 g (28%); mass
spectroscopy: [M+H].sup.+=178.
1-(2,6-dimethyl-benzyl)-cyclopropylamine
The compound is prepared according to general method 1 from 5.8 g
(40 mmol) (2,6-dimethyl-phenyl)-acetonitrile. Yield: 1.4 g (20%);
mass spectroscopy: [M+H].sup.+=176.
1-(2,4,6-trimethyl-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.0 g (31 mmol)
(2,4,6-trimethyl-phenyl)-acetonitrile. Yield: 2.2 g (37%); mass
spectroscopy: [M+H].sup.+=190.
1-(2,4-dimethyl-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.0 g (34 mmol)
(2,4-dimethyl-phenyl)-acetonitrile. Yield: 1.9 g (32%); mass
spectroscopy: [M+H].sup.+=176.
1-(2,6-dichloro-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.2 g (27 mmol)
(2,6-dichloro-phenyl)-acetonitrile. Yield: 2.7 g (46%); mass
spectroscopy: [M+H].sup.+=216/218/220.
1-(2-trifluoromethyl-benzyl)-cyclopropylamine
The amine is according to general method 1 from 5.0 g (27 mmol)
(2-trifluoromethyl-phenyl)-acetonitrile prepared. Yield: 2.8 g
(48%); mass spectroscopy: [M+H].sup.+=216.
1-(3-methyl-benzyl)-cycloproplylamine
Prepared according to general method 1 from 5.4 g (40 mmol)
m-tolyl-acetonitrile. Yield: 1.7 g (26%); mass spectroscopy:
[M+H].sup.+=162.
1-(2-methyl-benzyl)-cyclopropylamine
Prepared according to general method 1 from 3.5 mL (28 mmol)
o-tolyl-acetonitrile. Yield: 0.58 g (13%); mass spectroscopy:
[M+H].sup.+=162.
1-(3,5-dimethyl-benzyl)-cyclopropylamine
Prepared according to general method 1 from 5.9 g (40 mmol)
(3,5-dimethyl-phenyl)-acetonitrile. Yield: 3.8 g (54%); mass
spectroscopy: [M+H].sup.+=176.
1-(3,4-dimethyl-benzyl)-cyclopropylamine
The amine is obtained according to general method 1 from 5.9 g (40
mmol) (3,4-dimethyl-methyl-phenyl)-acetonitrile. Yield: 2.4 g
(34%); mass spectroscopy: [M+H].sup.+=176.
1-benzyl-cyclopropylamine
Prepared according to general method 1 from 4.7 g (40 mmol)
phenyl-acetonitrile. Yield: 2.3 g (39%); mass spectroscopy:
[M+H].sup.+=148.
1-(4-methoxy-benzyl)-cyclopropylamine
The amine is obtained according to general method 1 from 5.5 mL (40
mmol) (4-methoxy-phenyl)-acetonitrile. Yield: 4.2 g (59%); mass
spectroscopy: [M+H].sup.+=178.
1-phenoxymethyl-cyclopropylamine
The amine is obtained according to general method 1 from 3.94 g (29
mmol) phenoxy-acetonitrile. Yield: 1.80 g (38%); mass spectroscopy:
[M+H].sup.+=164.
1-(2,6-dimethyl-phenoxymethyl)-cyclopropylamine
The amine is obtained according to general method 1 from 4.80 g (30
mmol) (2,6-dimethyl-phenoxy)-acetonitrile. Yield: 2.56 g (45%);
mass spectroscopy: [M+H].sup.+=192.
1-[2-(4-methoxy-phenyl)-ethyl]-cyclopropylamine
Prepared according to general method 1 from 5.00 g (31 mmol)
3-(4-methoxy-phenyl)-propionitrile. Yield: 1.90 g (32%); mass
spectroscopy: [M+H].sup.+=192.
1-naphthalen-2-ylmethyl-cyclopropylamine
The amine is prepared according to general method 1 from 5.75 g (33
mmol) naphthalen-2-yl-acetonitrile. Yield: 2.30 g (35%); mass
spectroscopy: [M+H].sup.+=198.
1-(4-benzyloxy-benzyl)-cyclopropylamine
The compound is prepared analogously to general method 1 from 25 g
(112 mmol) naphthalen-2-yl-acetonitrile. Yield: 14.1 g (50%); mass
spectroscopy: [M+H].sup.+=254.
4-(1-amino-cyclopropylmethyl)-phenol
Hydrogenation of 5.00 g (19.7 mmol)
1-(4-benzyloxy-benzyl)-cyclopropylamine in 60 mL methanol at 3 bar
with palladium on charcoal as catalyst. Yield: 2.25 g (70%); mass
spectroscopy: [M+H].sup.+=164.
1-(2-naphthalen-1-yl-ethyl)-cyclopropylamine
The amine is prepared according to general method 1 from 5.4 g (30
mmol) 3-naphthalen-1-yl-propionitrile. Yield: 2.2 g (35%); mass
spectroscopy: [M+H].sup.+=212.
1-(4-chloro-phenoxymethyl)-cyclopropylamine
The amine is prepared according to general method 1 from 4.86 g (29
mmol) (4-chloro-phenoxy)-acetonitrile. Yield: 2.7 g (47%); mass
spectroscopy: [M+H].sup.+=198/200.
[4-(1-amino-cyclopropylmethyl)-phenyl]-dibenzyl-amine
Reaction of 32 g (102 mmol) (4-dibenzylamino-phenyl)-acetonitrile
according to general method 1. Yield: 14.1 g (40%); mass
spectroscopy: [M+H].sup.+=343.
4-(1-amino-cyclopropylmethyl)-phenylamine
3.0 g (8.8 mmol)
[4-(1-amino-cyclopropylmethyl)-phenyl]-dibenzyl-amine are dissolved
in 30 mL methanol and hydrogenated at 3 bar in the presence of
palladium on charcoal. Then the catalyst is filtered off and the
filtrate is evaporated down. The residue is dissolved in diethyl
ether and combined with 4 molar hydrochloric acid in dioxane. After
the solvent has been distilled off the hydrochloride is suspended
in diisopropylether for further purification.
Yield: 1.5 g (86%; hydrochloride); mass spectroscopy:
[M+H].sup.+=163/65.
General Method 2 (Synthesis of cyclopentyl- and
cyclohexylamines)
A solution of 1 equivalent (usually 70 mmol) ketone in 70 mL THF is
added dropwise at -20.degree. C. to 1.1 equivalents Grignard
reagent in THF. After 30 minutes stirring at ambient temperature
the reaction is stopped by the addition of ammonium chloride
solution and the mixture is extracted with dichloromethane. The
organic phases are dried with sodium sulphate and freed from
solvent. The residue is further reacted directly without any
further purification.
For this the alcohol and 8.7 mL (69.5 mmol) trimethylsilylcyanide
are combined at 10.degree. C. with 10.7 mL acetic acid. Then 14 mL
conc. sulphuric acid is added dropwise so that the temperature does
not exceed 20.degree. C. After two hours' stirring at ambient
temperature 140 mL 6 molar sodium hydroxide solution and 100 mL
tert-butylether are added. The organic phase is separated off,
dried with sodium sulphate and evaporated down. The formamide
present as an oil is dissolved in 16 mL ethanol, combined with 50
mL of a 20 molar sodium hydroxide solution and refluxed overnight.
After cooling to ambient temperature and adding toluene the phases
are separated. The organic phase is washed with water, dried with
sodium sulphate and freed from the solvent. The residue is
dissolved in ethyl acetate and combined with 10% hydrochloric acid
in ethyl acetate until an acid reaction takes place. The
precipitated hydrochloride is filtered off and dried.
1-phenethyl-cyclohexylamine
Prepared from 2.0 g (20.4 mmol) cyclohexanone and
phenethylmagnesium chloride (1 molar solution in tetrahydrofuran)
according to general method 2. Yield: 1.44 g (29%; hydrochloride).
Mass spectroscopy: [M+H].sup.+=204.
1-benzyl-cyclopentylamine
Prepared from 2.3 g (27.3 mmol) cyclopentanone and benzylmagnesium
chloride (2 molar solution in tetrahydrofuran) according to general
method 2.
Yield: 1.56 g (27%; hydrochloride). Mass spectroscopy:
[M+H].sup.+=176.
1-(4-Fluorobenzyl)-cyclopentylamine
Prepared from 2.7 g (32.1 mmol) cyclopentanone and
4-fluorobenzylmagnesium chloride (0.25 molar solution in
tetrahydrofuran) according to general method 2.
Yield: 3.72 g (50%; hydrochloride). Mass spectroscopy:
[M+H].sup.+=194.
1-[2-(4-methoxyphenyl)-ethyl]-cyclohexylamine
Prepared from 4.0 g (40.7 mmol) cyclohexanone and
4-methoxyphenethylmagnesium chloride (2 molar solution in
tetrahydrofuran) according to general method 2.
Yield: 2.53 g (23%; hydrochloride). Mass spectroscopy:
[M+H].sup.+=234.
1-(4-methoxy-benzyl)-cyclopentylamine
4-(1-amino-cyclopentylmethyl)-phenylamine
A solution of 2.1 g (8.4 mmol)
1-nitro-4-(1-nitrocyclopentylmethyl)-benzene (prepared according to
the prescribed method of Hass et. al., J. Org. Chem. 1949, 71,
2290-2291) in 60 mL methanol is hydrogenated with Raney Nickel as
catalyst at 3 bar. Then the catalyst is filtered off and the
filtrate freed from the solvent. The residue is dissolved in 15 mL
ethanol and combined with 10% hydrochloric acid in ethanol until an
acid reaction takes place. After removal of the solvents by
distillation the residue is suspended in 20 mL ethanol and
filtered.
Yield: 1.4 g (hydrochloride).
1-(4-methoxy-benzyl)-cyclopentylamine
1.4 g (6.17 mmol) 4-(1-aminocyclopentylmethyl)-phenylamine
hydrochloride are placed in 25 mL methanol and at 0.degree. C.
combined with 2.24 mL (27 mmol) conc. hydrochloric acid. At this
temperature 0.51 g (7.41 mmol) sodium nitrite in 1 mL water are
added dropwise within 30 minutes. After 2 hours stirring the
reaction mixture is allowed to come up to ambient temperature and
then refluxed for 3 hours. The solvents are distilled off and the
residue is combined with ethyl acetate. It is washed with aqueous
ammonia solution, dried with sodium sulphate and evaporated down.
The residue is dissolved in ethanol and combined with 10%
hydrochloric acid in ethanol. The product precipitated as a salt is
filtered off, washed with ethanol and dried. Yield: 0.56 g (27%
over 2 steps, hydrochloride), mass spectroscopy:
[M+H].sup.+=206.
1-(4-methoxy-benzyl)-cyclohexylamine
Obtained from 4.7 g (17.8 mmol) of
1-nitro-4-(1-nitro-cyclohexylmethyl)-benzene (prepared according to
the prescribed method of H. B. Hass et al., J. Org. Chem. 1949, 71,
2290-2291) analogously to the method described hereinbefore. Yield:
3.85 g (84%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=220.
1-[2-(4-fluoro-phenyl)-ethyl]-cyclohexylamine
2.5 g (11.3 mmol) 1-fluoro-4-iodo-benzene, 1.5 g (11.9 mmol)
1-ethynyl-cyclohexylamine, 793 mg (1.13 mmol)
PdCl.sub.2(PPh.sub.3).sub.2, 67 mg (0.35 mmol) copper iodide and 50
mL diisopropylamine are stirred for 2 hours at 70.degree. C. Then
the base is distilled off and the residue is combined with ethyl
acetate. The insoluble constituents are filtered off and the
filtrate is evaporated down. The alkyne thus prepared is dissolved
in 35 mL THF and 35 mL toluene and hydrogenated with platinum oxide
as catalyst at normal pressure. The catalyst is separated off and
the filtrate is freed from the solvent. The crude product is
dissolved in ethyl acetate and combined with 10% hydrochloric acid
in ethyl acetate. The precipitated solid is filtered off and washed
with ethyl acetate. Yield: 1.3 g (45%; hydrochloride); mass
spectroscopy: [M+H].sup.+=222.
Synthesis of the Compounds of General Formula 1:
General Method 3:
1 mmol glyoxalaldehyde or -acetal and 1 mmol amine are stirred for
30 minutes in 5 mL tetrahydrofuran at ambient temperature. The
mixture is cooled to 0.degree. C. and under an argon atmosphere 1.5
mL of a 2 molar solution of lithium borohydride in tetrahydrofuran
is added dropwise thereto. The mixture is stirred for 30 min at
ambient temperature, combined with 10 mL dichloromethane and 3 mL
water, stirred for a further hour and then filtered through
kieselguhr, while eluting with dichloromethane. The eluate is freed
from the solvent and the residue is purified by chromatography, if
necessary. The benzylether thus obtained is dissolved in methanol
and hydrogenated with palladium on charcoal (10%) as catalyst at
2.5 bar and ambient temperature. Then the catalyst is separated off
and the crude product is purified by chromatography (reverse phase,
acetonitrile/water gradient with 0.1% trifluoroacetic acid) or
recrystallised from acetonitrile.
General Method 4 (debenzylation with boron tribromide)
1 mmol glyoxalaldehyde or -acetal and 1 mmol amine are first of all
reacted and worked up as described in General Method 3. Then the
benzylether obtained is dissolved in 3 mL dichloromethane and
cooled to -78.degree. C. At this temperature 2 mL of a 1 molar
boron tribromide solution in dichloromethane is slowly added
dropwise. The reaction mixture is brought to ambient temperature,
stirred for a further 10 minutes and then diluted with 3 mL water
and 10 mL dichloromethane. The solution is added to a short column
filled with kieselguhr and washed again with dichloromethane and
methanol. The eluate is evaporated down and the residue is
chromatographed (reverse phase, acetonitrile/water gradient with
0.1% trifluoroacetic acid).
EXAMPLE 1
5-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one
##STR00012##
Reaction of 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
177 mg (1 mmol) 1-(4-methoxy-benzyl)-cyclopropylamine according to
general method 3. Yield: 39 mg (8%, trifluoroacetate); mass
spectroscopy: [M+H].sup.+=385.
EXAMPLE 2
8-[2-(1-benzyl-cyclopropylamino)-1-hydroxy-ethyl]-5-hydroxy-4H-benzo[1,4]o-
xazin-3-one
##STR00013##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
147 mg (1 mmol) 1-benzyl-cyclopropylamine. Yield: 56 mg (12%,
trifluoroacetate); mass spectroscopy: [M+H].sup.+=355.
EXAMPLE 3
8-{2-[1-(2,6-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00014##
The compound is prepared according to general method 3 from 329 mg
(1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
175 mg (1 mmol) 1-(2,6-dimethyl-benzyl)-cyclopropylamine. Yield: 52
mg (11%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=383.
EXAMPLE 4
8-{2-[1-(3,4-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00015##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
175 mg (1 mmol) 1-(3,4-dimethyl-benzyl)-cyclopropylamine. Yield:
233 mg (47%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=383.
EXAMPLE 5
5-hydroxy-8-{1-hydroxy-2-[1-(3-methyl-benzyl)-cyclopropylamino]-ethyl}-4H--
benzo[1,4]oxazin-3-one
##STR00016##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
161 mg (1 mmol) 1-(3-methyl-benzyl)-cyclopropylamine. Yield: 179 mg
(37%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=369.
EXAMPLE 6
5-hydroxy-8-{1-hydroxy-2-[1-(2-trifluoromethyl-benzyl)-cyclopronylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one
##STR00017##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
215 mg (1 mmol) 1-(2-trifluoromethyl-benzyl)-cyclopropylamine.
Yield: 13 mg (2%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=423.
EXAMPLE 7
5-hydroxy-8-(1-hydroxy-2-{1-[4-(1-hydroxy-cyclopropyl)-benzyl]-cyclopropyl-
amino}-ethyl)-4H-benzo1,4]oxazin-3-one
##STR00018##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
203 mg (1 mmol)
1-[4-(1-amino-cyclopropylmethyl)-phenyl]-cyclopropanol. Yield: 29
mg (6%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=411.
EXAMPLE 8
8-{2-[1-(3,5-difluoro-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00019##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
183 mg (1 mmol) 1-(3,5-difluoro-benzyl)-cyclopropylamine. Yield: 66
mg (13%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=391.
EXAMPLE 9
5-hydroxy-8-[1-hydroxy-2-(1-phenoxymethyl-cyclopropylamino)-ethyl]-4H-benz-
o[1,4]oxazin-3-one
##STR00020##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
163 mg (1 mmol) 1-phenoxymethyl-cyclopropylamine. Yield: 26 mg (5%,
trifluoroacetate); mass spectroscopy: [M+H].sup.+=371.
EXAMPLE 10
5-hydroxy-8-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopropylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one
##STR00021##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
215 mg (1 mmol) 1-(4-trifluoromethyl-benzyl)-cyclopropylamine.
Yield: 18 mg (3%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=423.
EXAMPLE 11
5-hydroxy-8-{1-hydroxy-2-[1-(2-methoxy-benzyl)-cyclopropylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one
##STR00022##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
177 mg (1 mmol) 1-(2-methoxy-benzyl)-cyclopropylamine. Yield: 100
mg (20%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=385.
EXAMPLE 12
5-hydroxy-8-{1-hydroxy-2-[1-(2-methyl-benzyl)-cyclopropylamino]-ethyl}-4H--
benzo[1,4]oxazin-3-one
##STR00023##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
161 mg (1 mmol) 1-(2-methyl-benzyl)-cyclopropylamine. Yield: 60 mg
(16%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=369.
EXAMPLE 13
8-{2-[1-(2,6-dimethyl-phenoxymethyl)-cyclopropylamino]-1-hydroxy-ethyl}-5--
hydroxy-4H-benzo[1,4]oxazin-3-one
##STR00024##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
191 mg (1 mmol) 1-(2,6-dimethyl-phenoxymethyl)-cyclopropylamine.
Yield: 194 mg (49%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=399.
EXAMPLE 14
5-hydroxy-8-[1-hydroxy-2-(1-naphthalen-2-ylmethyl-cyclopropylamino)-ethyl]-
-4H-benzo[1,4]oxazin-3-one
##STR00025##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
197 mg (1 mmol) 1-naphthalen-2-ylmethyl-cyclopropylamine. Yield: 20
mg (5%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=405.
EXAMPLE 15
8-{2-[1-(2,4-dimethyl-benzyl)-cyclopronylamino]-1-hydroxy-ethyl}-5-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00026##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
175 mg (1 mmol) 1-(2,4-dimethyl-benzyl)-cyclopropylamine. Yield:
176 mg (36%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=383.
EXAMPLE 16
5-hydroxy-8-{1-hydroxy-2-[1-(2,3,5,6-tetramethyl-benzyl)-cyclopropylamino]-
-ethyl}-4H-benzo[1,4]oxazin-3-one
##STR00027##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
203 mg (1 mmol) 1-(2,3,5,6-tetramethyl-benzyl)-cyclopropylamine.
Yield: 93 mg (18%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=411.
EXAMPLE 17
5-hydroxy-8-(1-hydroxy-2-{1-[2-(4-methoxy-phenyl)-ethyl]-cyclopropylamino}-
-ethyl)-4H-benzo[1,4]oxazin-3-one
##STR00028##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
191 mg (1 mmol) 1-[2-(4-methoxy-phenyl)-ethyl]-cyclopropylamine.
Yield: 55 mg (11%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=399.
EXAMPLE 18
8-{2-[1-(2,6-difluoro-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00029##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
183 mg (1 mmol) 1-(2,6-difluoro-benzyl)-cyclopropylamine. Yield:
108 mg (21%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=391.
EXAMPLE 19
8-{2-[1-(4-amino-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-4H-b-
enzo[1,4]oxazin-3-one
##STR00030##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
342 mg (1 mmol)
[4-(1-amino-cyclopropylmethyl)-phenyl]-dibenzyl-amine. Yield: 49 mg
(10%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=370.
EXAMPLE 20
5-hydroxy-8-{1-hydroxy-2-[1-(4-hydroxy-benzyl)-cyclopropylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one
##STR00031##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
253 mg (1 mmol) 1-(4-benzyloxy-benzyl)-cyclopropylamine. Yield: 20
mg (4%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=371.
EXAMPLE 21
8-{2-[1-(3,4-dimethoxy-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydrox-
y-4H-benzo[1,4]oxazin-3-one
##STR00032##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
207 mg (1 mmol) 1-(3,4-dimethoxy-benzyl)-cyclopropylamine. Yield:
15 mg (3%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=415.
EXAMPLE 22
8-{2-[1-(4-ethoxy-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-4H--
benzo[1,4]oxazin-3-one
##STR00033##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
191 mg (1 mmol) 1-(4-ethoxy-benzyl)-cyclopropylamine. Yield: 17 mg
(3%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=399.
EXAMPLE 23
8-{2-[1-(4-butoxy-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-5-hydroxy-4H--
benzo[1,4]oxazin-3-one
##STR00034##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
219 mg (1 mmol) 1-(4-butoxy-benzyl)-cyclopropylamine. Yield: 107 mg
(20%, trifluoroacetate); mass spectroscopy: [M+H].sup.+=427.
EXAMPLE 24
5-hydroxy-8-{1-hydroxy-2-[1-(2,4,6-trimethyl-benzyl)-cyclopropylamino]-eth-
yl}-4H-benzo[1,4]oxazin-3-one
##STR00035##
Prepared according to general method 3 from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
189 mg (1 mmol) 1-(2,4,6-trimethyl-benzyl)-cyclopropylamine. Yield:
26 mg (5%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=397.
EXAMPLE 25
5-hydroxy-8-{1-hydroxy-2-[(1-phenyl-cyclopropylmethyl)-amino]-ethyl}-4H-be-
nzo[1,4]oxazin-3-one
##STR00036##
Prepared from 329 mg (1 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
147 mg (1 mmol) C-(1-phenyl-cyclopropyl)-methylamine. Final
purification by chromatography (silica gel;
dichloromethane/methanol gradient). Yield: 30 mg (8%); mass
spectroscopy: [M+H].sup.+=355.
EXAMPLE 26
5-hydroxy-8-{1-hydroxy-2-[1-(2-naphthalen-2-yl-ethyl)-cyclopropylamino]-et-
hyl}-4H-benzo[1,4]oxazin-3-one
##STR00037##
Prepared from
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
1-(2-naphthalen-2-yl-ethyl)-cyclopropylamine. Mass spectroscopy:
[M+H].sup.+=419.
General Method 5:
1 mmol of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate
and 1 mmol amine are stirred for 30 minutes in 5 mL tetrahydrofuran
at ambient temperature. The mixture is cooled to 0.degree. C. and
under an argon atmosphere 1.5 mL of a 2 molar solution of lithium
borohydride in tetrahydrofuran are added dropwise. After 30 minutes
stirring at ambient temperature a further 1.5 mL of the 2 molar
solution of lithium borohydride in tetrahydrofuran are added and
the reaction solution is heated to 50.degree. C. for 4 hours. It is
combined with 10 mL dichloromethane and 3 mL water, stirred for a
further hour and then through filtered kieselguhr, while eluting
with dichloromethane. The eluate is evaporated down and the residue
is dissolved in methanol and hydrogenated in the presence of
palladium on charcoal (10%) at 2.5 bar and ambient temperature.
Then the catalyst is separated off and the crude product is
purified by chromatography (reverse phase, acetonitrile/water
gradient with 0.1% trifluoroacetic acid).
EXAMPLE 27
2-hydroxymethyl-4-{1-hydroxy-2-[(1-phenyl-cyclopropylmethyl)-amino]-ethyl}-
-phenol
##STR00038##
Prepared from 344 mg (1 mmol) methyl
2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 147 mg (1
mmol) 1-phenyl-cyclopropyl-methylamine. In a departure from General
Method 5 the target compound is purified by chromatography on a
silica gel column (dichloromethane/methanol gradient).
Yield: 162 mg (52%); mass spectroscopy: [M+H].sup.+=314.
EXAMPLE 28
4-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-2-hydroxymet-
hyl-phenol
##STR00039##
Prepared according to general method 5 from 344 mg (1 mmol) methyl
2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 177 mg (1
mmol) 1-(4-methoxy-benzyl)-cyclopropylamine. Yield: 123 mg (27%,
trifluoroacetate); mass spectroscopy: [M+H].sup.+=344.
EXAMPLE 29
4-[2-(1-benzyl-cyclopropylamino)-1-hydroxy-ethyl]-2-hydroxymethyl-phenol
##STR00040##
Prepared according to general method 5 from 344 mg (1 mmol) methyl
2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 147 mg (1
mmol) 1-benzyl-cyclopropylamine. Yield: 184 mg (43%,
trifluoroacetate); mass spectroscopy: [M+H].sup.+=314.
EXAMPLE 30
4-{2-[1-(2,6-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-2-hydroxy-
methyl-phenol
##STR00041##
Prepared according to general method 5 from 344 mg (1 mmol) methyl
2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 175 mg (1
mmol) 1-(2,6-dimethyl-benzyl)-cyclopropylamine. Yield: 64 mg (14%,
trifluoroacetate); mass spectroscopy: [M+H].sup.+=342.
EXAMPLE 31
6-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one
##STR00042##
Prepared from 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 177 mg (1 mmol) 1-(4-methoxyoxy-benzyl)-cyclopropylamine.
Yield: 109 mg (22%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=385.
EXAMPLE 32
6-hydroxy-8-{1-hydroxy-2-[1-(4-hydroxy-benzyl)-cyclopropylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one
##STR00043##
Prepared according to general method 3 from 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 253 mg (1 mmol) 1-(4-benzyloxy-benzyl)-cyclopropylamine. Yield:
47 mg (10%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=371.
EXAMPLE 33
6-hydroxy-8-{1-hydroxy-2-[(1-phenyl-cyclopropylmethyl)-amino]-ethyl}-4H-be-
nzo[1,4]oxazin-3-one
##STR00044##
Prepared from 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 147 mg (1 mmol) (1-phenyl-cyclopropyl)-methylamine. Yield: 138
mg (39%); mass spectroscopy: [M+H].sup.+=355.
EXAMPLE 34
8-{2-[1-(2,6-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00045##
Obtained from 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 175 mg (1 mmol) 1-(2,6-dimethyl-benzyl)-cyclopropylamine.
Yield: 93 mg (19%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=383.
EXAMPLE 35
8-{2-[1-(3,5-dimethyl-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00046##
Prepared from 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 175 mg (1 mmol) 1-(3,5-dimethyl-benzyl)-cyclopropylamine
according to general method 3.
Yield: 155 mg (31%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=383.
EXAMPLE 36
6-hydroxy-8-{1-hydroxy-2-[1-(4-trifluoromethoxy-benzyl)-cyclopropylamino]--
ethyl}-4H-benzo[1,4]oxazin-3-one
##STR00047##
Prepared from 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 231 mg (1 mmol) 1-(4-trifluoromethoxy-benzyl)-cyclopropylamine
according to general method 3.
Yield: 148 mg (27%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=439.
EXAMPLE 37
8-{2-[1-(2,4-dichloro-benzyl)-cyclopropylamino]-1-hydroxy-ethyl}-6-hydroxy-
-4H-benzo[1,4]oxazin-3-one
##STR00048##
458 mg (0.73 mmol) benzylether are obtained as the trifluoroacetate
from the reaction of 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 216 mg (1 mmol) 1-(2,4-dichloro-benzyl)-cyclopropylamine. The
subsequent debenzylation is carried out according to general method
4 with boron tribromide.
Yield: 158 mg (29% over 2 steps; trifluoroacetate); mass
spectroscopy: [M+H].sup.+=423/5/7.
EXAMPLE 38
8-{2-[1-(4-chloro-phenoxymethyl)-cyclopropylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one
##STR00049##
The reaction of 357 mg (1 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 198 mg (1 mmol) 1-(4-chloro-phenoxymethyl)-cyclopropylamine
yields 259 mg (0.4 mmol) benzylether (trifluoroacetate). This is
debenzylated according to general method 4 with boron
tribromide.
Yield: 99 mg (19% over 2 steps; trifluoroacetate); mass
spectroscopy: [M+H].sup.+=405/7.
Examples 39 to 42 are carried out according to general method 3
except that there is no need to cleave the benzyl protective group.
The yields given refer in each case to the reaction of 1 mmol of
1-(4-amino-3,5-dichloro-phenyl)-2,2-dihydroxy-ethanone and 1 mmol
of amine.
EXAMPLE 39
1-(4-amino-3,5-dichloro-phenyl)-2-[(1-phenyl-cyclopropylmethyl)-amino}-eth-
anol
##STR00050##
Yield: 63 mg (14%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=351/353/355.
EXAMPLE 40
1-(4-amino-3,5-dichloro-phenyl)-2-[1-(2,6-dimethyl-benzyl)-cyclopropylamin-
o]-ethanol
##STR00051##
Yield: 101 mg (21%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=379/381/383.
EXAMPLE 41
1-(4-amino-3,5-dichloro-phenyl)-2-[1-(4-methoxy-benzyl)-cyclopropylamino]--
ethanol
##STR00052##
Yield: 167 mg (34%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=381/383/385.
EXAMPLE 42
1-(4-amino-3,5-dichloro-phenyl)-2-(1-benzyl-cyclopropylamino)-ethanol
Yield: 271 mg (58%, trifluoroacetate); mass spectroscopy:
[M+H].sup.+=351/353/355.
##STR00053##
EXAMPLE 43
8-hydroxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-1H-
-quinolin-2-one
##STR00054##
a)
8-benzyloxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethy-
l}-1H-quinolin-2-one
587 mg (2.0 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 480
mg (2.7 mmol) 1-(4-methoxy-benzyl)-cyclopropylamine are refluxed in
10 mL n-butanol for 10 hours. Then the solvent is distilled off and
the residue is purified by chromatography (reverse phase,
water/acetonitrile gradient). Yield: 259 mg (27%); mass
spectroscopy: [M+H].sup.+=471.
b)
8-hydroxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-
-1H-quinolin-2-one
258 mg (0.51 mmol)
8-benzyloxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopropylamino]-ethyl}-
-1H-quinolin-2-one in 10 mL methanol are hydrogenated with
palladium on charcoal as catalyst at 3 bar. Then the catalyst is
separated off, the solvent is distilled off and the residue is
purified by chromatography (reverse phase, water/acetonitrile
gradient). Yield: 12 mg (6%); mass spectroscopy:
[M+H].sup.+=381.
EXAMPLE 44
8-hydroxy-5-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopronylamino]-e-
thyl}-1H-quinolin-2-one
##STR00055##
a)
8-benzyloxy-5-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopropylami-
no]-ethyl}-1H-quinolin-2-one
Reaction of 587 mg (2.0 mmol)
8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 710 mg (3.3 mmol)
1-(4-trifluoromethyl-benzyl)-cyclopropylamine is carried out
analogously to Example 40a43a). Yield: 322 mg (32%); mass
spectroscopy: [M+H].sup.+=509.
b)
8-hydroxy-5-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopropylamino-
]-ethyl}-1H-quinolin-2-one
322 mg (0.63 mmol)
8-benzyloxy-5-{1-hydroxy-2-[1-(4-trifluoromethyl-benzyl)-cyclopropylamino-
]-ethyl}-1H-quinolin-2-one are dissolved in 10 mL methanol and
hydrogenated in the presence of palladium on charcoal at 3 bar. The
precipitated product is dissolved by adding methanol. The catalyst
is separated off and the filtrate is evaporated down. The
precipitated solid is filtered off and suspended in diethyl ether
for further purification. Yield: 161 mg (61%); mass spectroscopy:
[M+H].sup.+=419.
General Method 6
7 mmol of the amine present as the hydrochloride are stirred with
1.7 mmol triethylamine for 30 minutes in 6 mL tetrahydrofuran. Then
1.7 mmol glyoxylaldehyde or -acetal is added and the mixture is
stirred for a further 1.5 hours. The reaction mixture is cooled to
10.degree. C., combined with 150 mg (6.9 mmol) lithium borohydride,
stirred for 30 minutes and then combined with water. Then the
mixture is extracted with dichloromethane and the organic phase is
dried with sodium sulphate. The solvent is distilled off and the
residue is dissolved in ethyl acetate and combined with 10%
hydrochloric acid in ethyl acetate. The precipitated solid is
filtered off, placed in methanol and hydrogenated with palladium on
charcoal at normal pressure. Then the catalyst is separated off and
the filtrate is freed from the solvent. By stirring the residue in
ethyl acetate or crystallising from the same solvent the product is
obtained in the form of a colourless solid.
EXAMPLE 45
6-hydroxy-8-[1-hydroxy-2-(1-phenethyl-cyclohexylamino)-ethyl]-4H-benzo[1,4-
]oxazin-3-one
##STR00056##
Prepared according to general method 6 from 607 mg (1.70 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 408 mg (1.70 mmol) 1-phenethylcyclohexylamine
hydrochloride.
Yield: 289 mg (38%, hydrochloride), mass spectroscopy:
[M+H].sup.+=411.
EXAMPLE 46
8-[2-(1-benzyl-cyclopentylamino)-1-hydroxy-ethyl]-6-hydroxy-4H-benzo[1,4]o-
xazin-3-one
##STR00057##
Prepared according to general method 6 from 607 mg (1.70 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 360 mg (1.70 mmol) 1-benzylcyclopentylamine hydrochloride.
Yield: 421 mg (59%, hydrochloride), mass spectroscopy:
[M+H].sup.+=383.
EXAMPLE 47
8-{2-[1-(4-fluoro-benzyl)-cyclopentylamino]-1-hydroxy-ethyl}-6-hydroxy-4H--
benzo[1,4]oxazin-3-one
##STR00058##
Prepared according to general method 6 from 607 mg (1.70 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 414 mg (1.70 mmol) 1-(4-fluoro-benzyl)-cyclopentylamine
hydrochloride.
Yield: 447 mg (60%, hydrochloride), mass spectroscopy:
[M+H].sup.+=401.
EXAMPLE 48
6-hydroxy-8-(1-hydroxy-2-{1-[2-(4-methoxy-phenyl)-ethyl]-cyclohexylamino}--
ethyl)-4H-benzo[1,4]oxazin-3-one
##STR00059##
Prepared according to general method 6 from 607 mg (1.70 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 458 mg (1.70 mmol)
1-[2-(4-methoxy-phenyl)-ethyl]-cyclohexylamine hydrochloride.
Yield: 559 mg (65%, hydrochloride), mass spectroscopy:
[M+H].sup.+=441.
EXAMPLE 49
6-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopentylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one
##STR00060##
Prepared from 607 mg (1.70 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 411 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclopentylamine
hydrochloride according to general method 6.
Yield: 428 mg (56%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=413.
EXAMPLE 50
6-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclohexylamino]-ethyl}-4H--
benzo[1,4]oxazin-3-one
##STR00061##
Obtained from 607 mg (1.70 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 435 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclohexylamine
hydrochloride according to general method 6.
Yield: 521 mg (66%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=427.
EXAMPLE 51
8-(2-{1-[2-(4-fluoro-phenyl)-ethyl]-cyclohexylamino}-1-hydroxy-ethyl)-6-hy-
droxy-4H-benzo[1,4]oxazin-3-one
##STR00062##
Prepared according to general method 6 from 607 mg (1.70 mmol)
6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one
and 438 mg (1.70 mmol) 1[2-(4-fluorophenyl)-ethyl]-cyclohexylamine
hydrochloride.
Yield: 507 mg (64%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=429.
EXAMPLE 52
5-hydroxy-8-[1-hydroxy-2-(1-phenethyl-cyclohexylamino)-ethyl]-4H-benzo[1,4-
]oxazin-3-one
##STR00063##
Obtained from 560 mg (1.70 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
408 mg (1.70 mmol) 1-phenethylcyclohexylamine hydrochloride
according to general method 6.
Yield: 320 mg (42%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=411.
EXAMPLE 53
8-[2-(1-benzyl-cyclopentylamino)-1-hydroxy-ethyl]-5-hydroxy-4H-benzo[1,4]o-
xazin-3-one
##STR00064##
Prepared from 560 mg (1.70 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
360 mg (1.70 mmol) 1-benzylcyclopentylamine hydrochloride according
to general method 6.
Yield: 328 mg (46%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=383.
EXAMPLE 54
8-{2-[1-(4-fluoro-benzyl)-cyclopentylamino]-1-hydroxy-ethyl}-5-hydroxy-4H--
benzo[1,4]oxazin-3-one
##STR00065##
Prepared from 560 mg (1.70 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
414 mg (1.70 mmol) 1-(4-fluoro-benzyl)-cyclopentylamine
hydrochloride according to general method 6.
Yield: 454 mg (61%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=401.
EXAMPLE 55
5-hydroxy-8-(1-hydroxy-2-{1-[2-(4-methoxy-phenyl)-ethyl]-cyclohexylamino}--
ethyl)-4H-benzo[1,4]oxazin-3-one
##STR00066##
Obtained from 560 mg (1.70 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
458 mg (1.70 mmol) 1-[2-(4-methoxy-phenyl)-ethyl]-cyclohexylamine
hydrochloride according to general method 6.
Yield: 544 mg (67%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=441.
EXAMPLE 56
5-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopentylamino]-ethyl}-4H-
-benzo[1,4]oxazin-3-one
##STR00067##
Prepared from 560 mg (1.70 mmol) of
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
411 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclopentylamine
hydrochloride according to general method 6.
Yield: 467 mg (61%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=413.
EXAMPLE 57
5-hydroxy-8-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclohexylamino]-ethyl}-4H--
benzo[1,4]oxazin-3-one
##STR00068##
Prepared from 560 mg (1.70 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
435 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclohexylamine
hydrochloride according to general method 6.
Yield: 426 mg (54%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=427.
EXAMPLE 58
8-(2-{1-[2-(4-fluoro-phenyl)-ethyl]-cyclohexylamino}-1-hydroxy-ethyl)-5-hy-
droxy-4H-benzo[1,4]oxazin-3-one
##STR00069##
Prepared from 560 mg (1.70 mmol)
5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and
438 mg (1.70 mmol) 1-[2-(4-fluoro-phenyl)-ethyl]-cyclohexylamine
hydrochloride according to general method 6.
Yield: 554 mg (70%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=429.
EXAMPLE 59
N-{2-hydroxy-5-[1-hydroxy-2-(1-phenethyl-cyclohexylamino)-ethyl]-phenyl}-m-
ethanesulphonamide
##STR00070##
Prepared from 645 mg (1.70 mmol)
N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide
and 408 mg (1.70 mmol) 1-phenethylcyclohexylamine hydrochloride
according to general method 6.
Yield: 336 mg (42%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=433.
EXAMPLE 60
N-{5-[2-(1-benzyl-cyclopentylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-met-
hanesulphonamide
##STR00071##
Prepared from 645 mg (1.70 mmol)
N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide
and 360 mg (1.70 mmol) 1-benzylcyclopentylamine hydrochloride
according to general method 6.
Yield: 346 mg (46%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=405.
EXAMPLE 61
N-(5-{2-[1-(4-fluoro-benzyl)-cyclopentylamino]-1-hydroxy-ethyl}-2-hydroxy--
phenyl)-methanesulphonamide
##STR00072##
Prepared from 645 mg (1.70 mmol)
N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide
and 414 mg (1.70 mmol) 1-(4-fluoro-benzyl)-cyclopentylamine
hydrochloride according to general method 6. Yield: 485 mg (62%,
hydrochloride). Mass spectroscopy: [M+H].sup.+=423.
EXAMPLE 62
N-[2-hydroxy-5-(1-hydroxy-2-{1-[2-(4-methoxy-phenyl)-ethyl]-cyclohexylamin-
o}-ethyl)-phenyl]-methanesulphonamide
##STR00073##
Obtained from 645 mg (1.70 mmol)
N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide
and 458 mg (1.70 mmol)
1-[2-(4-methoxy-phenyl)-ethyl]-cyclohexylamine hydrochloride
according to general method 6. Yield: 544 mg (64%, hydrochloride).
Mass spectroscopy: [M+H].sup.+=463.
EXAMPLE 63
N-(2-hydroxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclopentylamino]-ethyl}-
-phenyl)-methanesulphonamide
##STR00074##
Prepared from 645 mg (1.70 mmol)
N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide
and 411 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclopentylamine
hydrochloride according to general method 6. Yield: 369 mg (46%,
hydrochloride). Mass spectroscopy: [M+H].sup.+=435.
EXAMPLE 64
N-(2-hydroxy-5-{1-hydroxy-2-[1-(4-methoxy-benzyl)-cyclohexylamino]-ethyl}--
phenyl)-methanesulphonamide
##STR00075##
Prepared from 645 mg (1.70 mmol)
N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide
and 435 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclohexylamine
hydrochloride according to general method 6.
Yield: 562 mg (68%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=449.
EXAMPLE 65
N-[5-(2-{1-[2-(4-fluoro-phenyl)-ethyl]-cyclohexylamino}-1-hydroxy-ethyl)-2-
-hydroxy-phenyl]-methanesulphonamide
##STR00076##
Prepared from 645 mg (1.70 mmol)
N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide
and 438 mg (1.70 mmol)
1-[2-(4-fluoro-phenyl)-ethyl]-cyclohexylamine hydrochloride
according to general method 6.
Yield 614 mg (74%, hydrochloride). Mass spectroscopy:
[M+H].sup.+=451.
As has been found, the compounds of formula 1 are characterised by
their wide range of applications in the therapeutic field.
Particular mention should be made of those applications for which
the compounds of formula 1 according to the invention are
preferably used on the basis of their pharmaceutical activity as
betamimetics.
These include, for example, the treatment of inflammatory and
obstructive respiratory complaints, the inhibition of premature
labour in midwifery (tocolysis), the restoration of the sinus
rhythm in the heart in cases of atrio-ventricular block as well as
the correcting of bradycardic heart rhythm disorders
(antiarrhythmic agent), the treatment of circulatory shock
(vasodilatation and increasing the heart-time volume) as well as
the treatment of itching and skin inflammation.
The compounds according to the invention may be used particularly
in the treatment of respiratory complaints. In a preferred aspect
the present invention therefore relates to the use of compounds of
general formula 1 for preparing a pharmaceutical composition for
the treatment of respiratory complaints selected from the group
comprising obstructive pulmonary diseases of various origins,
pulmonary emphysema of various origins, restrictive pulmonary
diseases, interstitial pulmonary diseases, cystic fibrosis,
bronchitis of various origins, bronchiectasis, ARDS (adult
respiratory distress syndrome) and all forms of pulmonary
oedema.
The compounds of general formula 1 are preferably used for
preparing a pharmaceutical composition for the treatment of
obstructive pulmonary diseases selected from among bronchial
asthma, paediatric asthma, severe asthma, acute asthma attacks,
chronic bronchitis and COPD (chronic obstructive pulmonary
disease), while it is particularly preferable according to the
invention to use them for preparing a pharmaceutical composition
for the treatment of bronchial asthma and COPD.
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of
pulmonary emphysema which has its origins in COPD (chronic
obstructive pulmonary disease) or .alpha.1-proteinase inhibitor
deficiency.
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of
restrictive pulmonary diseases selected from among allergic
alveolitis, restrictive pulmonary diseases triggered by
work-related noxious substances, such as asbestosis or silicosis,
and restriction caused by lung tumours, such as for example
lymphangiosis carcinomatosa, bronchoalveolar carcinoma and
lymphomas.
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of
interstitial pulmonary diseases selected from among pneumonia
caused by infections, such as for example infection by viruses,
bacteria, fungi, protozoa, helminths or other pathogens,
pneumonitis caused by various factors, such as for example
aspiration and left heart insufficiency, radiation-induced
pneumonitis or fibrosis, collagenoses, such as for example lupus
erythematodes, systemic sclerodermy or sarcoidosis, granulomatoses,
such as for example Boeck's disease, idiopathic interstitial
pneumonia or idiopathic pulmonary fibrosis (IPF).
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of cystic
fibrosis or mucoviscidosis.
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of
bronchitis, such as for example bronchitis caused by bacterial or
viral infection, allergic bronchitis and toxic bronchitis.
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of
bronchiectasis.
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of ARDS
(adult respiratory distress syndrome).
It is also preferable to use compounds of general formula 1 for
preparing a pharmaceutical composition for the treatment of
pulmonary oedema, for example toxic pulmonary oedema after
aspiration or inhalation of toxic substances and foreign
substances.
Particularly preferably, the present invention relates to the use
of the compounds of formula 1 for preparing a pharmaceutical
composition for the treatment of asthma or COPD. Also of particular
importance is the above-mentioned use of compounds of formula 1 for
preparing a pharmaceutical composition for once-a-day treatment of
inflammatory and obstructive respiratory complaints, particularly
for the once-a-day treatment of asthma or COPD.
Suitable preparations for administering the compounds of formula 1
include tablets, capsules, suppositories, solutions, powders, etc.
The proportion of pharmaceutically active compound or compounds
should be in the range from 0.05 to 90% by weight, preferably 0.1
to 50% by weight of the total composition. Suitable tablets may be
obtained, for example, by mixing the active substance(s) with known
excipients, for example inert diluents such as calcium carbonate,
calcium phosphate or lactose, disintegrants such as corn starch or
alginic acid, binders such as starch or gelatine, lubricants such
as magnesium stearate or talc and/or agents for delaying release,
such as carboxymethyl cellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise several
layers.
Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, arabic gum,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number or
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations
of active substances according to the invention may additionally
contain a sweetener such as saccharine, cyclamate, glycerol or
sugar and a flavour enhancer, e.g. a flavouring such as vanillin or
orange extract. They may also contain suspension adjuvants or
thickeners such as sodium carboxymethyl cellulose, wetting agents
such as, for example, condensation products of fatty alcohols with
ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions are prepared in the usual way, e.g. with the addition of
isotonic agents, preservatives such as p-hydroxybenzoates, or
stabilisers such as alkali metal salts of ethylenediamine
tetraacetic acid, optionally using emulsifiers and/or dispersants,
whilst if water is used as the diluent, for example, organic
solvents may optionally be used as solvating agents or dissolving
aids, and transferred into injection vials or ampoules or infusion
bottles.
Capsules containing one or more active substances or combinations
of active substances may for example be prepared by mixing the
active substances with inert carriers such as lactose or sorbitol
and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with
carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
Excipients which may be used include, for example, water,
pharmaceutically acceptable organic solvents such as paraffins
(e.g. petroleum fractions), vegetable oils (e.g. groundnut or
sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or
glycerol), carriers such as e.g. natural mineral powders (e.g.
kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane
sugar, lactose and glucose), emulsifiers (e.g. lignin, spent
sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone)
and lubricants (e.g. magnesium stearate, talc, stearic acid and
sodium lauryl sulphate).
For oral administration the tablets may, of course, contain, apart
from the abovementioned carriers, additives such as sodium citrate,
calcium carbonate and dicalcium phosphate together with various
additives such as starch, preferably potato starch, gelatine and
the like. Moreover, lubricants such as magnesium stearate, sodium
lauryl sulphate and talc may be used at the same time for the
tabletting process. In the case of aqueous suspensions the active
substances may be combined with various flavour enhancers or
colourings in addition to the excipients mentioned above.
When the compounds of formula 1 are used, as preferred according to
the invention, for the treatment of asthma or COPD, it is
particularly preferable to use preparations or pharmaceutical
formulations that can be administered by inhalation. Suitable
formulations for inhalation include inhalable powders,
propellant-driven metered--dose aerosols or propellant-free
inhalable solutions. Within the scope of the present invention the
term propellant-free inhalable solutions also includes concentrates
or sterile ready-to-use inhalable solutions. The formulations which
may be used within the scope of the present invention are described
in detail in the next part of the specification.
The inhalable powders which may be used according to the invention
may contain 1 either on their own or in admixture with suitable
physiologically acceptable excipients.
If the active substances 1 are present in admixture with
physiologically acceptable excipients, the following
physiologically acceptable excipients may be used to prepare these
inhalable powders according to the invention: monosaccharides (e.g.
glucose or arabinose), disaccharides (e.g. lactose, saccharose,
maltose), oligo- and polysaccharides (e.g. dextrans), polyalcohols
(e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium carbonate) or mixtures of these excipients. Preferably,
mono- or disaccharides are used, while the use of lactose or
glucose is preferred, particularly, but not exclusively, in the
form of their hydrates. For the purposes of the invention, lactose
is the particularly preferred excipient, while lactose monohydrate
is most particularly preferred.
Within the scope of the inhalable powders according to the
invention the excipients have a maximum average particle size of up
to 250 .mu.m, preferably between 10 and 150 .mu.m, most preferably
between 15 and 80 .mu.m. In some cases it may seem appropriate to
add finer excipient fractions with an average particle size of 1 to
9 .mu.m to the excipient mentioned above. These finer excipients
are also selected from the group of possible excipients listed
hereinbefore. Finally, in order to prepare the inhalable powders
according to the invention, micronised active substance 1,
preferably with an average particle size of 0.5 to 10 .mu.m, more
preferably from 1 to 5 .mu.m, is added to the excipient mixture.
Processes for producing the inhalable powders according to the
invention by grinding and micronising and finally mixing the
ingredients together are known from the prior art.
The inhalable powders according to the invention may be
administered using inhalers known from the prior art.
The inhalation aerosols containing propellant gas according to the
invention may contain the compounds 1 dissolved in the propellant
gas or in dispersed form. The compounds 1 may be contained in
separate formulations or in a common formulation, in which the
compounds 1 are either both dissolved, both dispersed or in each
case only one component is dissolved and the other is dispersed.
The propellant gases which may be used to prepare the inhalation
aerosols are known from the prior art. Suitable propellant gases
are selected from among hydrocarbons such as n-propane, n-butane or
isobutane and halohydrocarbons such as fluorinated derivatives of
methane, ethane, propane, butane, cyclopropane or cyclobutane. The
above-mentioned propellant gases may be used on their own or in
admixture. Particularly preferred propellant gases are halogenated
alkane derivatives selected from TG134a and TG227 and mixtures
thereof.
The propellant-driven inhalation aerosols may also contain other
ingredients such as co-solvents, stabilisers, surfactants,
antioxidants, lubricants and pH adjusters. All these ingredients
are known in the art.
The propellant-driven inhalation aerosols according to the
invention mentioned above may be administered using inhalers known
in the art (MDIs=metered dose inhalers).
Moreover, the active substances 1 according to the invention may be
administered in the form of propellant-free inhalable solutions and
suspensions. The solvent used may be an aqueous or alcoholic,
preferably an ethanolic solution. The solvent may be water on its
own or a mixture of water and ethanol. The relative proportion of
ethanol compared with water is not limited but the maximum is
preferably up to 70 percent by volume, more particularly up to 60
percent by volume and most preferably up to 30 percent by volume.
The remainder of the volume is made up of water. The solutions or
suspensions containing 1 are adjusted to a pH of 2 to 7, preferably
2 to 5, using suitable acids. The pH may be adjusted using acids
selected from inorganic or organic acids. Examples of particularly
suitable inorganic acids include hydrochloric acid, hydrobromic
acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples
of particularly suitable organic acids include ascorbic acid,
citric acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid and/or propionic acid etc.
Preferred inorganic acids are hydrochloric and sulphuric acids. It
is also possible to use the acids which have already formed an acid
addition salt with one of the active substances. Of the organic
acids, ascorbic acid, fumaric acid and citric acid are preferred.
If desired, mixtures of the above acids may be used, particularly
in the case of acids which have other properties in addition to
their acidifying qualities, e.g. as flavourings, antioxidants or
complexing agents, such as citric acid or ascorbic acid, for
example. According to the invention, it is particularly preferred
to use hydrochloric acid to adjust the pH.
If desired, the addition of editic acid (EDTA) or one of the known
salts thereof, sodium edetate, as stabiliser or complexing agent
may be omitted in these formulations. Other embodiments may contain
this compound or these compounds. In a preferred embodiment the
content based on sodium edetate is less than 100 mg/100 ml,
preferably less than 50 mg/100 ml, more preferably less than 20
mg/100 ml. Generally, inhalable solutions in which the content of
sodium edetate is from 0 to 10 mg/100 ml are preferred.
Co-solvents and/or other excipients may be added to the
propellant-free inhalable solutions. Preferred co-solvents are
those which contain hydroxyl groups or other polar groups, e.g.
alcohols--particularly isopropyl alcohol, glycols--particularly
propyleneglycol, polyethyleneglycol, polypropyleneglycol,
glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene
fatty acid esters. The terms excipients and additives in this
context denote any pharmacologically acceptable substance which is
not an active substance but which can be formulated with the active
substance or substances in the physiologically suitable solvent in
order to improve the qualitative properties of the active substance
formulation. Preferably, these substances have no pharmacological
effect or, in connection with the desired therapy, no appreciable
or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya
lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilisers, complexing agents,
antioxidants and/or preservatives which guarantee or prolong the
shelf life of the finished pharmaceutical formulation, flavourings,
vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium
chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic
acid, for example, provided that it has not already been used to
adjust the pH, vitamin A, vitamin E, tocopherols and similar
vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from
contamination with pathogens. Suitable preservatives are those
which are known in the art, particularly cetyl pyridinium chloride,
benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in the concentration known from the prior art. The
preservatives mentioned above are preferably present in
concentrations of up to 50 mg/100 ml, more preferably between 5 and
20 mg/100 ml.
Preferred formulations contain, in addition to the solvent water
and the active substance 1, only benzalkonium chloride and sodium
edetate. In another preferred embodiment, no sodium edetate is
present.
The dosage of the compounds according to the invention is naturally
highly dependent on the method of administration and the complaint
which is being treated. When administered by inhalation the
compounds of formula 1 are characterised by a high potency even at
doses in the jig range. The compounds of formula 1 may also be used
effectively above the .mu.g range. The dosage may then be in the
milligram range, for example.
In another aspect the present invention relates to the
above-mentioned pharmaceutical formulations as such, which are
characterised in that they contain a compound of formula 1,
particularly preferably the above-mentioned pharmaceutical
formulations for use by inhalation.
The following formulation examples illustrate the present invention
without restricting its scope:
TABLE-US-00001 A) Ampoule solution active substance of formula 1 25
mg sodium chloride 50 mg water for inj. 5 ml
The active substance is dissolved in water at its own pH or
optionally at pH 5.5 to 6.5 and sodium chloride is added to make it
isotonic. The solution obtained is filtered free from pyrogens and
the filtrate is transferred under aseptic conditions into ampoules
which are then sterilised and sealed by fusion. The ampoules
contain 5 mg, 25 mg and 50 mg of active substance.
TABLE-US-00002 B) Metered-dose aerosol (suspension) active
substance of formula 1 0.03 wt. % sorbitolan trioleate 0.6 wt. %
HFA134A:HFA227 2:1 99.37 wt. %
The suspension is poured into a conventional aerosol container with
metering valve. Preferably 50 .mu.l suspension are delivered in
each puff. The active substance may if desired also be delivered in
higher doses.
TABLE-US-00003 C) Metered-dose aerosol (solution) active substance
of formula 1 0.03 wt. % ethanol abs. 20 wt. % aqueous HCl 0.01
mol/l 2.0 wt. % HFA134A 77.97 wt. %
The solution is prepared in the conventional manner by mixing the
individual constituents.
TABLE-US-00004 D) Inhalable powder active substance of formula 1 80
.mu.g lactose monohydrate ad 10 mg
The inhalable powder is prepared in the conventional manner by
mixing the individual constituents.
* * * * *